FR2802206A1 - 4-AMINOPIPERIDINE DERIVATIVES AND THEIR USE AS MEDICINAL PRODUCTS - Google Patents

Abstract

The present application relates to new derivatives of 4-aminopiperidines of formula (CF DRAWING IN BOPI) in which R1, R2 and R3 represent various variable groups, their preparation processes by parallel synthesis methods in liquid and solid phase. These products having a good affinity with certain subtypes of somatostatin receptors, they are particularly useful for treating pathological states or diseases in which one (or more) of the somatostatin receptors is (are) involved.

Description

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 The present application relates to novel 4-aminopiperidine derivatives and their methods of preparation by liquid and solid phase parallel synthesis methods. Since these products have a good affinity with certain somatostatin receptor subtypes, they are particularly useful for treating pathological conditions or diseases in which one or more somatostatin receptors are (are) involved.

Somatostatin (SST) is a cyclic tetradecapeptide that has been isolated for the first time from the hypothalamus as a growth hormone inhibitory substance (Brazeau P. et al., Science 1973, 179, 77-79). It is also involved as a neurotransmitter in the brain (Reisine T. et al., Neuroscience 1995, 67, 777-790, Reisine et al., Endocrinology 1995, 16, 427-442). Molecular cloning has shown that the bioactivity of somatostatin is directly dependent on a family of five membrane-bound receptors.

The heterogeneity of the biological functions of somatostatin has led to studies to try to identify the structure-activity relationships of peptide analogues on somatostatin receptors, which led to the discovery of 5 receptor subtypes (Yamada et al. al., Proc Natl Acad Sci USA, 89, 251-255, 1992, Raynor, K. et al., Mol Pharmacol., 44, 385-392, 1993). The functional roles of these receptors are currently actively studied. Affinities with the different subtypes of somatostatin receptors have been associated with the treatment of the following disorders / diseases. The activation of subtypes 2 and 5 has been associated with the suppression of growth hormone (GH) and more particularly that of adenomas secreting GH (acromegaly) and those secreting the hormone TSH.

Activation of subtype 2 but not subtype 5 has been associated with the treatment of prolactin-secreting adenomas. Other indications associated with the activation of somatostatin receptor subtypes are restenosis, inhibition of insulin and / or glucagon secretion and in particular diabetes mellitus, hyperlipidemia, insensitivity Insulin, Syndrome X, angiopathy,

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 proliferative retinopathy, the Dawn phenomenon and nephropathy; inhibition of gastric acid secretion and in particular peptic ulcers, enterocutaneous and pancreaticocutaneous fistulas, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS-related diarrhea, diarrhea-induced diarrhea chemotherapy, acute or chronic pancreatitis and secretory gastrointestinal tumors; cancer treatment such as hepatoma; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic rejection of allografts; prevention of bleeding from grafted vessels and gastrointestinal bleeding. Somatostatin agonists can also be used to decrease the weight of a patient.

Among the pathological disorders associated with somatostatin (Moreau JP et al., Life Sciences, 1987, 40, 419, Harris AG et al., The European Journal of Medicine, 1993, 2, 97-105), one can cite for example : acromegaly, pituitary adenomas, Cushing's disease, gonadotrophinomas and prolactinomas, catabolic side effects of glucocorticoids, insulin-dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrine gastroenteropancreatic tumors including carcinoid syndrome, VIPoma, insulinoma, neidioblastosis, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison syndrome, GRFome and acute bleeding of oesophageal varices, gastroesophageal reflux, gastroduodenal reflux, pancreatitis, enterocutaneous and pancreatic fistulas but also diarrhea, refractory diarrhea of the immuno acquired depression, chronic secretory diarrhea, diarrhea associated with irritated bowel syndrome, gastrin-releasing peptide-related disorders, pathologies secondary to intestinal grafts, portal hypertension and haemorrhages of varicose veins in patients with cirrhosis, gastrointestinal bleeding, peptic ulcer bleeding, Crohn's disease, systemic sclerosis, dumping syndrome, small bowel syndrome, hypotension, scleroderma and medullary thyroid carcinoma, diseases related to cell hyperproliferation such as cancers and more particularly breast cancer, prostate cancer, thyroid cancer as well as

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 pancreatic cancer and colorectal cancer, fibrosis and more particularly kidney fibrosis, liver fibrosis, lung fibrosis, fibrosis of the skin, fibrosis of the central nervous system as well as that of the nose and fibrosis induced by chemotherapy, and other therapeutic areas such as, for example, headaches including headaches associated with pituitary tumors, pain, panic attacks, chemotherapy, wound healing, renal failure resulting from stunting, obesity and growth retardation related to obesity, uterine growth retardation, skeletal dysplasia, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic disease ovaries, pancreatic pseudocysts and ascites, leukemia, meningioma, cancer cachexia, H pylori inhibition, psoriasis and Alzheimer's disease. We can also mention osteoporosis.

Applicants have found that the compounds of the general formula described below have affinity and selectivity for somatostatin receptors.

Since somatostatin and its peptide analogues often have poor oral bioavailability and low selectivity (Robinson, C., Drugs of the Future, 1994, 19, 992, Reubi, JC et al., TIPS, 1995, 16, 110 ), said non-peptide somatostatin agonists or antagonists may be advantageously used to treat the disease states or diseases as presented above and in which one (or more) of the somatostatin receptors are (are) (s) involved. Preferably, said compounds can be used for the treatment of acromegaly, pituitary adenomas or endocrine gastroenteropancreatic tumors including carcinoid syndrome.

The subject of the present invention is therefore compounds of general formula

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ou bien R1 représente un radical de formule

R2 représente un radical de formule -C(Y)NHX1, -C(O)X2 ou S02X3; R3 représente l'atome d'hydrogène, un radical alkyle éventuellement substitué, alkényle, alkynyle, aralkyle éventuellement susbtitué, hétéroarylalkyle éventuellement substitué, ou un radical de formule -C(Y)-NHX1' -(CH2)n-C(O)X2, S02X3 ou in racemic, enantiomeric form or any combination thereof, wherein: R1 represents a linear or branched (C1-C16) alkyl radical, alkenyl, alkynyl, - (CH2) mY-Z11 or - (CH2) m-Z12 in which
Z11 represents optionally substituted (C1-C6) alkyl or aryl,
Z12 represents cyano, cyclohexenyl, bis-phenyl, (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, or Z12 represents a radical of formula

or else R 1 represents a radical of formula

R2 represents a radical of formula -C (Y) NHX1, -C (O) X2 or SO2X3; R3 represents the hydrogen atom, an optionally substituted alkyl radical, alkenyl, alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or a radical of formula -C (Y) -NHX1 '- (CH2) nC (O) X2, S02X3 or

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X1 représente un radical (C1-C15)alkyle linéaire ou ramifié, alkényle, alkynyle, -(CH2)m-Y-Z21 ou -(CH2)pZ22 dans lequel
Z21 représente un (Cl-C6)alkyle
Z22 représente cyclohexényle, indanyle, bis-phényle, (C3-C7)cycloalkyle, (C3-C7)hétérocycloalkyle, mono- ou di-alkylamino, -C(O)-O-alkyle, ou aryle ou hétéroaryle éventuellement substitué, ou Z22 représente un radical de formule

X2 représente un radical (C1-C10)alkyle linéaire ou ramifié, alkényle éventuellement substitué par un radical phényle (le radical phényle étant lui-même éventuellement substitué), alkynyle, ou un radical de formule -(CH2)m-W-(CH2)q-Z23 ou -(CH2)p-U-Z24 dans lequel
Z23 représente un (Cl-C6)alkyle ou aryle éventuellement substitué ;
Z24 représente alkyle, cyclohexényle, bis-phényle, (C3-C7)cycloalkyle éventuellement substitué, (C3-C7)hétérocycloalkyle, cyano, amino, mono ou di-alkylamino, ou aryle ou hétéroaryle éventuellement substitué, ou Z24 représente un radical de formule

X1 represents a linear or branched (C1-C15) alkyl radical, alkenyl, alkynyl, - (CH2) mY-Z21 or - (CH2) pZ22 in which
Z21 represents a (C1-C6) alkyl
Z22 is cyclohexenyl, indanyl, bis-phenyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, mono- or di-alkylamino, -C (O) -O-alkyl, or optionally substituted aryl or heteroaryl, or Z22 represents a radical of formula

X2 represents a linear or branched (C1-C10) alkyl radical, alkenyl optionally substituted with a phenyl radical (the phenyl radical being itself optionally substituted), alkynyl, or a radical of formula - (CH2) mW- (CH2) q -Z23 or - (CH2) pU-Z24 in which
Z23 represents optionally substituted (C1-C6) alkyl or aryl;
Z24 represents alkyl, cyclohexenyl, bis-phenyl, optionally substituted (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, cyano, amino, mono or di-alkylamino, or optionally substituted aryl or heteroaryl, or Z24 represents a radical of formula

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ou bien X2 représente un radical représenté ci-dessous :

où le groupe protecteur (GP) représente H ou le tert-butyloxycarbonyle ;

or X 2 represents a radical represented below:

where the protecting group (GP) is H or tert-butyloxycarbonyl;

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éventuellement substitué par un ou plusieurs radicaux halo identiques ou différents ; Y représente un atome d'oxygène ou de soufre ; W représente un atome d'oxygène, de soufre ou SO2 ; U représente une liaison covalente ou l'atome d'oxygène ; n est un entier de 0 à 4 ; m est un entier de 1 à 6 ; p est un entier de 0 à 6 ; q est un entier de 0 à 2, ou leurs sels d'addition avec les acides minéraux ou organiques pharmaceutiquement acceptables. X3 represents a linear or branched (C1-C10) alkyl radical, alkenyl optionally substituted by a phenyl radical (the phenyl radical being itself optionally substituted), CF3, or - (CH2) pZ25 in which
Z25 represents optionally substituted aryl or heteroaryl, or X3 represents a radical of formula

optionally substituted with one or more identical or different halo radicals; Y represents an oxygen or sulfur atom; W represents an oxygen, sulfur or SO2 atom; U represents a covalent bond or the oxygen atom; n is an integer of 0 to 4; m is an integer of 1 to 6; p is an integer of 0 to 6; q is an integer of 0 to 2, or their addition salts with pharmaceutically acceptable inorganic or organic acids.

The invention more particularly relates to the products of general formula 1 as defined above, characterized in that i) the substituent (s) may carry the aryl radicals that represent Zn and Z12 and heteroaryl that represents Z12 are independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, -CF3, -OCF3, phenyl, phenoxy, aminosulfonyl; ii) the substituent (s) may carry the heterocycloalkyl radical represented by Z12 are independently selected from oxy and alkyl radicals;

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 iii) the substituent (s) which may carry the aryl and heteroaryl radicals represented by Z22 are independently chosen from fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano radicals, azido, aminosulfonyl, piperidinosulfonyl, mono- or di-alkylamino, -C (O) -O-alkyl, C (O) -alkyl, or phenyl, phenoxy, phenylthio, benzyloxy, the phenyl radical being substitutable; iv) the substituent (s) which can carry the aryl radicals represented by Z 23 and Z 24, cycloalkyl and heteroaryl represented by Z 24 are chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF 3 and OCF 3 radicals; , OCHF2, SCF3, nitro, cyano, azido, hydroxy, -C (O) O-alkyl, -OC (O) -alkyl, -NH-C (O) alkyl, alkylsulfonyl, mono- or di-alkylamino, amino, aminoalkyl, pyrrolyl, pyrrolydinyl or the phenyl, phenoxy, phenylthio, benzyl, benzyloxy radicals, the aryl radical of which is optionally substituted by one or more alkyl, CF3 or halo radicals; v) the substituent (s) may carry the aryl and heteroaryl radicals represented by Z25 are independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, nitro, cyano, -NH-C radicals ( O) -alkyl, alkylsulfonyl, amino, mono- and di-alkylamino, phenyl, pyridino; vi) the substituent that can bear the alkyl radical that represents R3 is the cyano radical. vii) the substituent (s) may bear the aralkyl radical represented by R3 are independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, OCHF2, SCF3, SCHF2, nitro, cyano, C (O) O-alkyl, alkylsulfonyl, thiadiazolyl, or the phenyl and phenoxy radicals, the phenyl radical of which is optionally substituted by one or more halo radicals. viii) the substituent (s) may bear the heteroarylalkyl radical represented by R3 are independently selected from fluoro, chloro, bromo or nitro radicals.

In the definitions given above, the expression halo represents the fluoro, chloro, bromo or iodo radical, preferably chloro, fluoro or bromo. Expression

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 alkyl (when not more precise), preferably represents an alkyl radical having from 1 to 6 carbon atoms, linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl or amyl, isopentyl, neopentyl, hexyl or isohexyl. Among the alkyl radicals containing from 1 to 15 carbon atoms, mention may be made of the alkyls as defined above, but also the heptyl, octyl, nonyl, decyl, dodecyl, tridecyl or pentadecyl radicals.

By alkenyl, when not more precise is meant a linear or branched alkyl radical having from 1 to 6 carbon atoms and having at least one unsaturation (double bond), for example vinyl, allyl, propenyl , butenyl or pentenyl. By alkynyl, when not more precise is meant a linear or branched alkyl radical having from 1 to 6 carbon atoms and having at least one double unsaturation (triple bond) such as for example an ethynyl, propargyl radical. , butynyl or pentynyl.

The term cycloalkyl denotes a monocyclic carbon system comprising from 3 to 7 carbon atoms, and preferably the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl rings. The term "heterocycloalkyl" refers to a saturated cycloalkyl containing from 2 to 7 carbon atoms and at least one heteroatom. This radical can contain several identical or different heteroatoms. Preferably, the heteroatoms are selected from oxygen, sulfur or nitrogen. As examples of heterocycloalkyl, mention may be made of the pyrrolidine, pyrrolidinone, imidazolidine, pyrrazolidine, isothiazolidine, thiazolidine, isoxazolidine, piperidine, piperazine or morpholine ring.

The alkoxy radicals may correspond to the alkyl radicals indicated above, for instance the methoxy, ethoxy, propyloxy or isopropyloxy radicals, but also linear, secondary or tertiary butoxy, pentyloxy radicals. The term lower alkylthio preferably denotes radicals in which the alkyl radical is as defined above such as, for example, methylthio, ethylthio. The term alkylsulfonyl preferably denotes radicals in which the alkyl radical is as defined above.

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The term "aryl" represents an aromatic radical consisting of a ring or condensed rings, such as, for example, the phenyl or naphthyl radical. The term heteroaryl refers to an aromatic radical, consisting of a ring or condensed rings, with at least one ring containing one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen. As an example of a heteroaryl radical, mention may be made of the thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, quinoxalinyl, benzothienyl, benzofuryl, indolyl and benzoxadiazoyl radicals. .

The terms mono- and di-alkylamino preferably denote radicals in which the alkyl radicals are as defined above, such as, for example, methylamino, ethylamino, dimethylamino, diethylamino or (methyl) (ethyl) amino.

Y représente l'atome d'oxygène, The present invention more particularly relates to compounds of general formula I as defined above in which: R1 represents a linear or branched (C1-C6) alkyl radical, the radical - (CH2) mY-Z11 or - (CH2 ) m -Z12 in which
Z11 represents a (C1-C6) alkyl,
Z12 represents bis-phenyl, (C3-C7) cycloalkyl, (C3-C7) optionally substituted heterocycloalkyl, or aryl or heteroaryl optionally substituted with one or more substituents chosen independently from fluoro, chloro, bromo, iodo, alkyl or alkoxy radicals, or else Z12 represents

Y represents the oxygen atom,

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R2 représente un radical de formule -C(Y)NHX1, -C(O)X2 ou S02X3 dans laquelle
X1 représente un radical (C1-C5)alkyle linéaire ou ramifié, ou-(CH2)pZ22 dans lequel
Z22 représente cyclohexényle, bis-phényle, (C3-C7)cycloalkyle, (C3-C7)hétérocycloalkyle, mono- ou di-alkylamino, -C(O)-O-alkyle, ou aryle ou hétéroaryle éventuellement substitué par un ou plusieurs radicaux choisis indépendamment parmi les radicaux fluoro, chloro, bromo, iodo, alkyle, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, pipéridinosulfonyle, -C(O)-O-alkyle, -C(O)-alkyle, ou phényle, ou bien Z22 représente un radical de formule

X2 représente un radical (C1-C10)alkyle linéaire ou ramifié, alkynyle, -(CH2)m-W-(CH2)q-Z23 ou -(CH2)p-U-Z24 dans lequel
W représente S02,
U représente une liaison covalente,
Z23 représente un radical aryle ;
Z24 représente cyclohexényle, bis-phényle, (C3-C7)cycloalkyle éventuellement substitué par un radical aminoalkyle, ou aryle ou hétéroaryle éventuellement substitué par un ou plusieurs radicaux choisis parmi fluoro, chloro, bromo, iodo, alkyle, alkoxy, -CF3, -OCF3, SCF3, hydroxy, -O-C(O)-alkyle, mono- ou di-alkylamino, amino ou Z24 représente un radical de formule or a radical of formula

R2 represents a radical of formula -C (Y) NHX1, -C (O) X2 or SO2X3 in which
X1 represents a linear or branched (C1-C5) alkyl radical, or- (CH2) pZ22 in which
Z22 is cyclohexenyl, bis-phenyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, mono- or di-alkylamino, -C (O) -O-alkyl, or aryl or heteroaryl optionally substituted with one or more radicals. independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulfonyl, -C (O) -O-alkyl, -C (O) -alkyl, or phenyl, or Z22 represents a radical of formula

X2 represents a linear or branched (C1-C10) alkyl radical, alkynyl, - (CH2) mW- (CH2) q-Z23 or - (CH2) pU-Z24 in which
W represents SO 2,
U represents a covalent bond,
Z23 represents an aryl radical;
Z24 represents cyclohexenyl, bis-phenyl, (C3-C7) cycloalkyl optionally substituted by an aminoalkyl radical, or aryl or heteroaryl optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, -CF3, - OCF3, SCF3, hydroxy, -OC (O) -alkyl, mono- or di-alkylamino, amino or Z24 represents a radical of formula

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ou bien X2 représente

or else X2 represents

X3 represents a radical - (CHpZ in which Z25 represents an aryl radical optionally substituted with one or more identical or different radicals chosen from alkoxy and CF3, R3 represents the hydrogen atom, an optionally substituted alkyl, alkenyl, heteroarylalkyl radical or a radical of formula -C (Y) -NHX1, -C (O) X2 or SO2X3 in which
X1 represents a radical - (CH2) pZ22 in which
Z22 represents an aryl radical optionally substituted by one or more radicals chosen independently from fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals;
X 2 represents the vinyl radical substituted with a phenyl, the phenyl radical being itself optionally substituted by one or more halo radicals, or - (CH 2) pU-Z 24 in which
Z24 represents alkyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, bisphenyl, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted with one or more radicals selected from

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alkoxy, bromo, chloro, fluoro, hydroxy, CF 3, nitro, amino, mono- and di-alkylamino, pyrrolyl, or X 2 represents a radical of formula

X3 represents a linear or branched (C1-C10) alkyl radical, the vinyl radical substituted by a radical (the phenyl radical being itself optionally substituted), CF3, or - (CH2) pZ25 in which
Z25 represents aryl or heteroaryl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, -NH-C (O) -alkyl, mono- and di-alkylamino radicals.

Preferably, R1 represents a linear or branched (C1-C6) alkyl radical, the radical - (CH2) mY-Z11 or - (CH2) m -Z124 in which
Z11 represents a (C1-C6) alkyl,
Z12 represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by the oxy radical, or the phenyl, piperazinyl, pyridinyl and indolyl radicals which are optionally substituted with one or more substituents chosen independently from the bromo, fluoro, chloro, alkyl radicals, alkoxy, -CF3, -OCF3;

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or else Z12 represents

De manière préférentielle, R2 représente un radical de formule -C(Y)NHX, -C(O)X2 ou S02X3 dans laquelle
X1 représente un radical (C1-C10)alkyle linéaire ou ramifié, ou-(CH2)pZ22 dans lequel Z22 représente cyclohexyle, cyclohexényle, bis-phényle, morpholino, pipéridino, mono- ou di-alkylamino, -C(O)-O-alkyle, ou phényle, naphtyle ou furyle éventuellement substitué par un ou plusieurs radicaux choisis indépendamment parmi les radicaux fluoro, chloro, bromo, iodo, alkyle, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, pipéridinosulfonyle, -C(O)-O-alkyle, -C(O)-alkyle ou phényle, ou bien Z22 représente un radical de formule

X2 représente un radical alkyle, alkynyle, -(CH2)m-W-(CH2)q-Z23 ou -(CH2)pZ24 dans lequel
W représente SO2 ; Z23 représente le radical phényle ;
Z24 représente cyclohexényle, bis-phényle, cyclohexyle éventuellement substitué par un radical aminoalkyle, ou phényle, naphtyle, benzothiényle, thiényle ou indolyle éventuellement substitué par un ou Y represents the oxygen atom, or R1 represents a radical of formula below:

Preferably, R2 represents a radical of formula -C (Y) NHX, -C (O) X2 or SO2X3 in which
X1 represents a linear or branched (C1-C10) alkyl radical, or- (CH2) pZ22 in which Z22 represents cyclohexyl, cyclohexenyl, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, -C (O) -O -alkyl, or phenyl, naphthyl or furyl optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulfonyl, -C ( O) -O-alkyl, -C (O) -alkyl or phenyl, or Z22 represents a radical of formula

X2 represents an alkyl, alkynyl, - (CH2) mW- (CH2) q-Z23 or - (CH2) pZ24 radical in which
W represents SO2; Z23 represents the phenyl radical;
Z 24 represents cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted with an aminoalkyl radical, or phenyl, naphthyl, benzothienyl, thienyl or indolyl optionally substituted with one or

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ou bien X2 représente

a plurality of radicals selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, -CF3, -OCF3, SCF3, hydroxy, -OC (O) -alkyl, -NH-C (O) -alkyl, mono- or di-alkylamino , amino, or Z24 represents a radical of formula

or else X2 represents

X3 represents a - (CH2) pZ25 radical in which Z25 represents the phenyl radical optionally substituted with one or more identical or different radicals chosen from alkoxy and CF3. Preferably, R3 represents the hydrogen atom, an alkyl radical or alkenyl radical. or furyl-methyl substituted with one or more nitro radicals, or a radical of formula -C (Y) -NHX 1 -C (O) X 2 or SO 2 X 3 in which
X1 represents a radical - (CH2) pZ22 in which
Z22 represents the phenyl or naphthyl radical optionally substituted with one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals,

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X 2 represents the vinyl radical substituted by a phenyl radical itself optionally substituted with one or more halo radicals, or - (CH 2) pU-Z 24 in which
Z 24 represents alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono or di-alkylamino, or phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl optionally substituted by one or more radicals chosen from alkoxy, bromo, chloro, fluoro, amino , mono- and di-alkylamino, nitro, hydroxy, pyrrolyl or X2 represents a radical of formula

X3 represents a linear or branched (C1-C10) alkyl radical, the vinyl radical substituted by a phenyl radical, CF3, or - (CH2) pZ25 in which
Z25 represents a phenyl, naphthyl, thienyl, pyrazolyl or thiazolyl radical optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, -NH-C (O) -alkyl radicals; mono- and di-alkylamino; Very preferably, R 1 represents the radical - (CH 2) m Z 12 in which m = 2 and Z 12 represents bis-phenyl or the indolyl radical substituted by one or more substituents chosen independently from the alkyl and alkoxy radicals.

Very preferably, R2 represents the radicals of formula -C (Y) NHXj and -C (O) X2 in which
Y is S;

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X 1 represents a phenyl radical optionally substituted with one or more azido radicals,
X2 is - (CH2) pZ24 wherein p is 1, 2 or 3,
Z24 represents cyclohexyl, or phenyl or benzothienyl optionally substituted with one or more radicals selected from fluoro, chloro, bromo, iodo or -CF3.

Very preferably, R3 represents the hydrogen atom or the methyl radical.

The compounds according to the invention can be prepared in solid or liquid phase.

dans laquelle R représente le radical méthyle ou Boc, en présence d'une amine de formule R1NH2 dans laquelle R1 a la signification indiquée ci-dessus, pour obtenir le composé de formule 1

composé de formule (1) que l'on fait réagir avec A) soit un composé de formule XiNC(Y) dans laquelle X, et Y ont la signification indiquée ci-dessus, pour obtenir un composé de formule (2) The subject of the invention is also a process for the preparation, in the liquid phase, of compounds of formula 1 according to the invention, characterized in that it comprises the reductive amination of the following N-substituted piperidone

in which R represents the methyl radical or Boc, in the presence of an amine of formula R 1 NH 2 in which R 1 has the meaning indicated above, to obtain the compound of formula 1

compound of formula (1) which is reacted with A) is a compound of formula XiNC (Y) wherein X, and Y have the meaning indicated above, to obtain a compound of formula (2)

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composé de formule (2) qui représente le composé de formule (I) correspondant dans lequel R3 représente Me ou Boc et qui, lorsque R3 représente Boc, peut être soumis à un traitement acide pour obtenir le composé de formule (I) correspondant dans laquelle R3 représente l'atome d'hydrogène, composé de formule (I) ainsi obtenu que l'on peut faire réagir avec un composé de formule X,NC(Y), X2CO2H ou bien X3SO2Cl dans laquelle X,, Y, X2 et X3 ont la signification indiquée ci-dessus, pour obtenir le composé de formule I correspondant dans laquelle R2 représente un radical de formule -C(Y)NHX, et R3 le radical-C(Y)NHX1, -C(O)X2 ou S02X3 respectivement ; B) soit un composé de formule X2CO2H dans laquelle X2 a la signification indiquée ci-dessus, pour obtenir un composé de formule (3)

composé de formule (3) qui représente le composé de formule (I) correspondant dans lequel R3 représente Me ou Boc et qui, lorsque R3 représente Boc, peut être soumis à un traitement acide pour obtenir le composé de formule (I) correspondant dans laquelle R3 représente l'atome d'hydrogène, composé de formule (I) ainsi obtenu que l'on peut faire réagir avec un composé de formule X,NC(Y), X2CO2H ou bien X3XO2Cl dans laquelle X,, Y, X2 et X3 ont la signification indiquée ci-dessus, pour obtenir le composé de formule 1 correspondant dans laquelle R2 représente un radical de formule -C(O)X2 et R3 le radical-C(Y)NHX1, -C(O)X2 ou SOZX3 respectivement.

compound of formula (2) which represents the corresponding compound of formula (I) wherein R3 is Me or Boc and which, when R3 is Boc, may be subjected to acid treatment to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom, compound of formula (I) thus obtained which can be reacted with a compound of formula X, NC (Y), X2CO2H or X3SO2Cl wherein X ,, Y, X2 and X3 have the meaning indicated above, to obtain the corresponding compound of formula I in which R2 represents a radical of formula -C (Y) NHX, and R3 the radical-C (Y) NHX1, -C (O) X2 or SO2X3 respectively ; B) a compound of formula X2CO2H wherein X2 has the meaning indicated above, to obtain a compound of formula (3)

compound of formula (3) which represents the corresponding compound of formula (I) wherein R3 is Me or Boc and which, when R3 is Boc, may be acid treated to obtain the corresponding compound of formula (I) wherein R3 represents the hydrogen atom, compound of formula (I) thus obtained which can be reacted with a compound of formula X, NC (Y), X2CO2H or X3XO2Cl in which X ,, Y, X2 and X3 have the meaning indicated above, to obtain the corresponding compound of formula 1 wherein R2 represents a radical of formula -C (O) X2 and R3 the radical-C (Y) NHX1, -C (O) X2 or SOZX3 respectively .

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en présence d'une amine de formule R1NH2 dans laquelle R1 a la signification indiquée ci-dessus, pour obtenir le composé de formule (4)

composé de formule (4) que l'on fait réagir avec A) soit un composé de formule X,NC(Y) dans laquelle X, et Y ont la signification indiquée ci-dessus, pour obtenir un composé de formule (5)

suivi du clivage de la résine pour obtenir le composé de formule (I) correspondant dans laquelle R3 représente l'atome d'hydrogène, B) soit un composé de formule X3SO2Cl dans laquelle X3 a la signification indiquée ci-dessus, pour obtenir un composé de formule (6) The subject of the invention is also a method for the preparation, in the solid phase, of compounds of formula 1 according to the invention, characterized in that it comprises the reductive amination of the ketonic resin.

in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated above, to obtain the compound of formula (4)

compound of formula (4) which is reacted with A) is a compound of formula X, NC (Y) wherein X, and Y have the meaning indicated above, to obtain a compound of formula (5)

followed by cleavage of the resin to obtain the corresponding compound of formula (I) wherein R3 represents hydrogen, B) is a compound of formula X3SO2Cl wherein X3 has the meaning indicated above, to obtain a compound of formula (6)

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suivi du clivage de la résine pour obtenir le composé de formule (I) correspondant dans laquelle R3 représente l'atome d'hydrogène, C) soit un composé de formule X2CO2Cl dans laquelle X2 a la signification indiquée ci-dessus, pour obtenir un composé de formule (7)

suivi du clivage de la résine pour obtenir le composé de formule (I) correspondant dans laquelle R3 représente l'atome d'hydrogène ; D) soit un composé de formule X2CO2H dans laquelle X2 a la signification indiquée ci-dessus, pour obtenir un composé de formule (7) tel que défini ci-dessus, suivi du clivage de la résine pour obtenir le composé de formule (I) correspondant dans laquelle R3 représente l'atome d'hydrogène.

followed by cleavage of the resin to obtain the corresponding compound of formula (I) wherein R3 represents hydrogen, C) is a compound of formula X2CO2Cl wherein X2 has the meaning indicated above, to obtain a compound of formula (7)

followed by cleavage of the resin to obtain the corresponding compound of formula (I) wherein R3 represents hydrogen; D) a compound of formula X2CO2H wherein X2 has the meaning indicated above, to obtain a compound of formula (7) as defined above, followed by cleavage of the resin to obtain the compound of formula (I) wherein R3 represents the hydrogen atom.

The subject of the invention is also a method for the preparation, in the solid phase, of compounds of formula 1 according to the invention, characterized in that it comprises the reductive amination of the ketonic resin.

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composé de formule (8) que l'on fait réagir avec A) soit un composé de formule X1NC(O) dans laquelle X, a la signification indiquée ci-dessus, pour obtenir un composé de formule (9)

composé (9) ainsi formé que l'on fait réagir avec un composé de formule R3X dans laquelle R3 est tel que défini ci-dessus et X représente Br ou I, suivi du clivage de la résine pour obtenir le composé de formule (I) correspondant ; B) soit un composé de formule X3SO2Cl dans laquelle X3 a la signification indiquée ci-dessus, pour obtenir un composé de formule (10)

composé (10) ainsi formé que l'on fait réagir avec un composé de formule R3X dans laquelle R3 est tel que défini ci-dessus et X représente Br ou I, suivi du clivage de la résine pour obtenir le composé de formule (I) correspondant ; in the presence of an amine of formula R 1 NH 2 in which R 1 has the meaning indicated above, to obtain the compound of formula (8)

compound of formula (8) which is reacted with A) is a compound of formula X1NC (O) wherein X, has the meaning indicated above, to obtain a compound of formula (9)

compound (9) thus formed which is reacted with a compound of formula R3X wherein R3 is as defined above and X is Br or I, followed by cleavage of the resin to obtain the compound of formula (I) corresponding; B) a compound of formula X3SO2Cl wherein X3 has the meaning indicated above, to obtain a compound of formula (10)

compound (10) thus formed which is reacted with a compound of formula R3X wherein R3 is as defined above and X is Br or I, followed by cleavage of the resin to obtain the compound of formula (I) corresponding;

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composé (11) ainsi formé que l'on fait réagir avec un composé de formule R3X dans laquelle R3 est tel que défini ci-dessus et X représente Br ou I, suivi du clivage de la résine pour obtenir le composé de formule (I) correspondant ; D) soit un composé de formule X2CO2H dans laquelle X2 a la signification indiquée ci-dessus, pour obtenir un composé de formule (11) tel que défini ci-dessus, composé (11) ainsi formé que l'on fait réagir avec un composé de formule R3X dans laquelle R3 est tel que défini ci-dessus et X représente Br ou I, suivi du clivage de la résine pour obtenir le composé de formule (I) correspondant. C) a compound of formula X2CO2Cl wherein X2 has the meaning indicated above, to obtain a compound of formula (11)

compound (11) thus formed which is reacted with a compound of formula R3X wherein R3 is as defined above and X is Br or I, followed by cleavage of the resin to obtain the compound of formula (I) corresponding; D) is a compound of formula X2CO2H wherein X2 has the meaning indicated above, to obtain a compound of formula (11) as defined above, compound (11) thus formed which is reacted with a compound of formula R3X wherein R3 is as defined above and X is Br or I, followed by cleavage of the resin to obtain the corresponding compound of formula (I).

dans laquelle R représente méthyle ou Boc et R, a la signification indiquée ci-dessus. A) Liquid phase syntheses via the N-substituted piperidone Al) Reductive amination It is carried out according to the following step:

in which R represents methyl or Boc and R, has the meaning indicated above.

The general procedure is as follows: reductive amination (Abdel-Magid, AF, Maryanoff, CA, Carson, KG Tetrahedron Lett 1990, 31, 5595-5598, Abdel-Magid, AF, Carson, KG, Harris, BD; Maryanoff, CA, Shah, RD, J. Org Chem., 1996, 61, 3849-3862) of the N-substituted piperidone is carried out in chlorinated anhydrous solvents such as dichloroethane in the presence of a primary amine (1.1 at 1.5 eq.), a reducing agent such as sodium triacetoxyborohydride (1.1

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 at 1.5 eq. ) and acetic acid (10% by weight relative to the N-substituted piperidone). The reaction mixture is stirred for 1 to 4 hours at room temperature. In some cases, a sodium hydroxide solution (0.1M) is added and the mixture is stirred for 20 to 90 minutes. Otherwise, the reaction mixture is washed with saturated sodium bicarbonate solution, sodium chloride, dried over magnesium sulfate, filtered and concentrated. The desired product is purified by flash chromatography on silica gel.

A 5 g (25 mmol) de N-Boc-pipéridone dans 100 ml de dichloroéthane sec est ajouté la 3,3-diphénylpropylamine (5,8 g, 27,5 mmol), le triacétoxyborohydrure de sodium (6,36 g, 30 mmol) et 0,5 ml d'acide acétique. La solution jaune trouble est agitée à température ambiante pendant 1 heure. 50 ml d'une solution de soude (0.1M) sont alors ajoutés et le mélange agité pendant 30 minutes. La phase organique est lavée avec une solution saturée de bicarbonate de sodium, de chlorure de sodium, séchée sur sulfate de magnésium, filtrée et concentrée pour donner 10 g d'un solide jaune. Preparation 1: 4 - [(3,3-Diphenylpropyl) amino] -1-piperidine tert-butylcarboxylate (C25H34N2O2, M = 394.56)

To 5 g (25 mmol) of N-Boc-piperidone in 100 ml of dry dichloroethane is added 3,3-diphenylpropylamine (5.8 g, 27.5 mmol), sodium triacetoxyborohydride (6.36 g, mmol) and 0.5 ml of acetic acid. The cloudy yellow solution is stirred at ambient temperature for 1 hour. 50 ml of a sodium hydroxide solution (0.1M) are then added and the mixture is stirred for 30 minutes. The organic phase is washed with a saturated solution of sodium bicarbonate, sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 10 g of a yellow solid.

This solid is purified by flash chromatography on silica gel, eluting with a heptane / ethyl acetate mixture (4 / 1.3 / 1, 2/1 and then 1/1) and then with pure ethyl acetate. Fractions are concentrated in vacuo to give 5.6 g (yield = 57%) of a pale yellow solid.

1 H NMR (CD 3 OD, 400 MHz): 7.27 (m, 8H); 7.16 (m, 2H); 4 (dd, J = 6.4 and 14Hz, 3H); 2.73 (m, 2H); (m, 3H); (q, J = 7.6 Hz, 2H); (d, J = 12Hz, 2H); 1.45 (s, 9H); 1.15 (qd, J = 4.4 and 12.8 Hz, 2H). MS / LC: mlz = 395.2 (M + H).

A series of 4-aminosubstituted-1-piperidine is prepared according to this procedure with the other R groups, as follows:

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A2) Fonctionalisation des pipéridines A2a) Synthèses d'urées et de thiourées Les synthèses d'urées et de thiourées sont mises en #uvre selon la procédure décrite dans la littérature (Kaldor, S.W. ; Siegel, M.G. ; Fritz, J.E. ; B.A. ; Hahn,P.J. Tetrahedron Lett. 1996, 37, 7193-7196 ; Kaldor, S.W. ; J.E. ; J. ; McKinney, E.R. Bioorg. Med. Chem. Lett. 1996, 6, 3041-3044 ; Booth, R.J. ; Hodges, J.C. J. Am. Chem. Soc. 1997, 119, 4882-4886 ; Flynn, D.L. ; J.Z. ; Devraj, R.V. ; S.L. ; J.J. ; M.S. ; S. J. Am.

A2) Functionalization of piperidines A2a) Synthesis of urea and thiourea The synthesis of urea and thiourea are carried out according to the procedure described in the literature (Kaldor, SW, Siegel, MG, Fritz, JE, BA, Hahn , PJ Tetrahedron Lett, 1996, 37, 7193-7196, Kaldor, SW, JE, McKinney, ER Bioorg, Med Chem, Lett, 1996, 6, 3041-3044, Booth, RJ, Hodges, JCJ Am. Chem Soc., 1997, 119, 4882-4886; Flynn, DL; JZ; Devraj, RV; SL; J; MS; SJ Am.

dans laquelle R représente méthyle ou Boc et X2 et Y ont la signification indiquée cidessus. Il est à noter que dans le cas où R représente Boc, le produit ainsi obtenu est un produit final répondant à la formule 1 selon l'invention mais peut également être utilisé comme intermédiaire de synthèse. Chem. Soc. 1997, 119, 4874-4881) according to the following scheme:

wherein R is methyl or Boc and X2 and Y are as defined above. It should be noted that in the case where R represents Boc, the product thus obtained is a final product corresponding to formula 1 according to the invention but can also be used as synthesis intermediate.

The general procedure is as follows: isocyanate or isothiocyanate (1.1 to 1.5 eq.) Is added to 4-aminosubstituted-1-piperidine in aprotic solvents such as dichloromethane, tetrahydrofuran or dimethylformamide and the mixture is stirred for 45 minutes to 18 hours at room temperature. The aminomethyl resin (Novabiochem, 1.33 mmol / g, 0.2 to 1 eq.) Is added and the stirred mixture of

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 45 minutes to 18 hours. In some cases, basic ion exchange resin such as IRA-68 (Gayo, L.M., Suto, M.J.Tetrahedron Lett., 1997, 38, 513-516) may be added. The resins are filtered and the filtrate concentrated. Other purifications on silica gel cartridge or basic alumina (500 mg, Interchim) can optionally be carried out.

A une solution de carboxylate de tert-butyl 4-[(3,3-diphénylpropyl)amino]-1- pipéridine (470 mg, 1,2 mmol) dans 5 ml de dichlorométhane est ajouté 246 mg (1,32 mmol) d'isocyanate de 3- (trifluorométhyl)phényle. solution est agitée 45 minutes, et la résine aminométhyle (180 mg, 0,36 mmol) est ajoutée et la réaction remise sur l'agitateur orbital pendant 45 minutes. La résine est filtrée et lavée au dichlorométhane. Le filtrat est concentré in vacuo pour donner 610 mg (rdt = 87 %) d'une mousse blanche. Example A2a: tert-Butyl-4 - ((3,3-diphenylpropyl) {[3- (trifluoromethyl) anilino] carbonyl} amino) -1-piperidine carboxylate

To a solution of tert-butyl 4 - [(3,3-diphenylpropyl) amino] -1-piperidine carboxylate (470 mg, 1.2 mmol) in 5 ml of dichloromethane is added 246 mg (1.32 mmol) of dichloromethane. 3- (trifluoromethyl) phenyl isocyanate. The solution was stirred for 45 minutes, and the aminomethyl resin (180 mg, 0.36 mmol) was added and the reaction returned to the orbital shaker for 45 minutes. The resin is filtered and washed with dichloromethane. The filtrate is concentrated in vacuo to give 610 mg (yield = 87%) of a white foam.

 1 H NMR (CD 3 OD, 400 MHz) #: 7.71 (s, 1H); 7.57 (d, 1H); 7.43 (t, 1H); (m, 10H); 7.15 (m, 1H); 4.1 (m, 3H); (dd, J = 7.6 and 10Hz, 1H); 3.17 (m, 2H); 2.75 (m, 2H); (m, 2H); (d, J = 12Hz, 2H); 1.46 (s, 9H, t-butyl group); 1.39 (dd, J = 2.4 and 10.8 Hz, 2H); 1.29 (s, 1H). MS / LC: m / z = 582 (M + H).

For the groups R 1 as illustrated in point A1 above, the groups X 1 which can be envisaged for the synthesis of ureas (Y = 0) according to the procedure above, are as follows:

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For groups R1 as illustrated in point A1 above, groups XI which can be envisaged for the synthesis of thioureas (Y = S) according to the procedure above, are as follows:

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A2b) Synthèse d'amides à partir d'acides carboxyliques Les synthèses d'amides à partir d'acides carboxyliques sont mises en #uvre selon le schéma réactionnel suivant :

dans laquelle R représente méthyle ou Boc et X2 a la signification indiquée ci-dessus.

A2b) Synthesis of Amides from Carboxylic Acids Syntheses of amides from carboxylic acids are carried out according to the following reaction scheme:

in which R represents methyl or Boc and X2 has the meaning indicated above.

It should be noted that in the case where R represents Boc, the product thus obtained is a final product corresponding to formula I according to the invention but can also be used as synthesis intermediate.

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 The general procedure is as follows: the carboxylic acid (1.1 to 2.5 eq.) Dissolved in an anhydrous aprotic solvent such as dichloromethane, dimethylformamide or tetrahydrofuran is activated with 1-ethyl-3- (3) resin-dimethylaminopropyl) carbodiimide (P-EDC, Novabiochem, 2.33 mmol, 1.3-3 eq.) (Desai, MC; Stramiello, LM Tetrahedron Lett., 1993, 34, 7685-7688).

This mixture is stirred for 5 to 30 minutes at room temperature. The 4-aminosubstituted-1-piperidine predissolved in an anhydrous aprotic solvent such as dichloromethane, dimethylformamide or tetrahydrofuran is then added and the reaction mixture stirred at room temperature for 1 to 18 hours. In some cases, basic ion exchange resin (IRA-68, SAX) is added and the mixture is again stirred at room temperature for 1 to 18 hours. The resins are filtered on a sintered or ion exchange basic resin cartridge (IRA-68, SAX) or on a basic alumina cartridge (500 mg, Interchim).

512 mg (1,12 mmol, 1,4 éq. ) de résine P-EDC est prégonflée dans le dichlorométhane. L'acide 2-(1H-indol-3-yl)acétique (153 mg, 0,875 mmol, 1,1 éq. ) est ajouté et le mélange agité 10 minutes. Le carboxylate de tert-butyl 4-[(3,3-diphénylpropyl)amino]-l-pipéridine (292 mg, 0,8 mmol) dans le tétrahydrofurane est ajouté et la réaction agitée toute la nuit. 2 spatules de résine basique échangeuse d'ions IRA-68 sont ajoutées et la réaction agitée à nouveau toute la nuit. Les résines sont filtrées et le filtrat est concentré sous vide pour donner 250 mg (rdt = 86 %) d'une mousse jaune pâle. Example A2b: tert-butyl 4 - {(3,4-dimethoxyphenethyl) [2- (1H-indol-3-yl) acetyl] amino} -1 -piperidine carboxylate (C35H41N3O3, M = 551.74)

512 mg (1.12 mmol, 1.4 eq) of P-EDC resin is pre-swollen in dichloromethane. 2- (1H-Indol-3-yl) acetic acid (153 mg, 0.875 mmol, 1.1 eq) is added and the mixture is stirred for 10 minutes. The tert-butyl carboxylate 4 - [(3,3-diphenylpropyl) amino] -1-piperidine (292 mg, 0.8 mmol) in tetrahydrofuran is added and the reaction stirred overnight. 2 spatulas of basic ion exchange resin IRA-68 are added and the reaction stirred again overnight. The resins are filtered and the filtrate is concentrated in vacuo to give 250 mg (yield = 86%) of a pale yellow foam.

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 1 H NMR (CD 3 OD, 400 MHz): 7.63 (d, J = 8 Hz, 1H); 7.44 (d, J = 8Hz, 1H); 7.36 (d, J = 8Hz, 1H); 7.26 (d, J = 8Hz, 1H); 7.2 (m, 6H); (m, 3H); (m, 2H); 6.68 (s, 1H); 4-3.75 (m, 4H); 3.65 (s, 1H); 3.2 (m, 1H); 3 (m, 1H); 2.75 (m, 1H); 2.26 (m, 3H); 1.6 (m, 2H); 1.44 (s, 9H); 1.13 (m, 2H). SMICL: mlz = 552.4 (M + H).

A series of amides was synthesized according to this procedure. The X2 radicals that can be considered are:

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où le groupe protecteur (GP) représente H ou tert-butyloxycarbonyle.

wherein the protecting group (GP) is H or tert-butyloxycarbonyl.

A3) Syntheses of 4-aminodisubstituted piperidines The synthesis of the 4-aminodisubstituted piperidines according to the invention can be carried out by acid treatment of the N-Boc compounds described above, according to the following reaction scheme:

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Procédure générale : deux méthodes ont été utilisées pour effectuer la déprotection en milieu acides des urées, thiourées et amides précédemment décrits. La première consiste à dissoudre le composé dans du dichlorométhane et additionner l'acide trifluoroacétique (5 à 20 éq. ) tandis que dans la seconde une solution d'acide chlorhydrique dilué dans des solvants tels que l'acétate d'éthyle, le dioxane ou le diéthyléther (5 à 20 éq. ) est utilisée. La réaction est agitée 1 à 4 heures à température ambiante. Dans certains cas, du dichlorométhane est ajouté et la phase organique est lavée avec une solution saturée de bicarbonate de sodium, séchée sur sulfate de magnésium, filtrée et concentrée sous vide pour isoler la base libre.

General procedure: two methods were used to carry out the deprotection in acidic medium of ureas, thioureas and amides previously described. The first is to dissolve the compound in dichloromethane and add trifluoroacetic acid (5 to 20 eq.) While in the second a solution of hydrochloric acid diluted in solvents such as ethyl acetate, dioxane or diethyl ether (5 to 20 eq) is used. The reaction is stirred for 1 to 4 hours at room temperature. In some cases, dichloromethane is added and the organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo to isolate the free base.

Example A3: N- (3,3-Diphenylpropyl) -N- (4-piperidinyl) -N '- [3- (trifluoromethyl) phenyl] urea (C28H30F3N3O, M = 481.57)

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 To a solution of tert-butyl4 - ((3,3-diphenylpropyl) {[3- (trifluoromethyl) anilino] carbonyl} amino) -1-piperidine carboxylate (600 mg, 1.04 mmol) in dichloromethane is added 1 6 ml (21 mmol, 20 eq) of trifluoroacetic acid. The reaction is stirred for 90 minutes and then concentrated. Dichloromethane is added and the organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo to isolate 490 mg (yield = 98%) of a white foam.

1 H NMR (CD 3 OD, 400 MHz) δ: 7.7 (s, 1H); 7.55 (d, 1H); (t, 1H); 7.28 (m, 9H); 7.18 (m, 2H); (m, 2H); (m, 2H); 3.11 (d, J = 10.8 Hz, 2H); 2.7 (td, J = 2.4 and 12.4Hz, 2H); 2.38 (q, J = 8Hz, 2H); (d, J = 10 Hz, 2H); 1.63 (qd, J = 4 and 12.4 Hz, 2H). MS / LC: m / z = 482.2 (M + H).

A series of 4-aminopiperidines was synthesized according to this procedure. The radicals R 1, X 1 and X 2 that can be envisaged are those already illustrated at points A1 and A2 above.

 B) Solid Phase Synthesis of 4-Aminopiperidines 4-Aminopiperidines were prepared by solid phase synthesis starting from Wang resin.

Cette résine a été préparée à partir de la résine de Wang (fournie par Bachem ou Novabiochem) avec des taux de charge supérieurs à 0.89mmol/g, suivant la procédure décrite dans la littérature (Bunin, B.A. The Combinatorial Index, Academic Press, 1998, p. 62-63 ; Dressman, B.A. ; Spangle, L.A. ; Kaldor, S.W. Bl) Preparation of the resin Bla) Preparation of the p-nitrophenyl carbonate resin of Wang It is carried out according to the following scheme

This resin was prepared from Wang resin (supplied by Bachem or Novabiochem) with filler levels greater than 0.89 mmol / g, following the procedure described in the literature (Bunin, BA The Combinatorial Index, Academic Press, 1998). , 62-63; Dressman, BA; Spangle, LA; Kaldor, SW

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 Tetrahedron Lett. 1996, 37, 937-940; Hauske, J.R .; Tetrahedron Lett.

1995, 36, 1589-1592; Cao, J.; Cuny, G.D .; J.R. Molecular Diversity 1998, 3, 173-179): N-methylmorpholine or pyridine and 4-nitrophenyl chloroformate are successively added to the pre-swollen Wang resin in dichloromethane or tetrahydrofuran at room temperature. The mixture is stirred all night. The resin is washed with tetrahydrofuran, diethyl ether and dichloromethane and then dried in vacuo at 50 ° C overnight.

Au chlorhydrate hydraté de pipéridone dilué dans de la diméthylformamide est ajoutée de la triéthylamine (1éq.) et du tamis moléculaire. Le mélange est chauffé jusqu'à dissolution complète de la cétone. Cette solution est ajoutée à la résine carbonate de p-nitrophényle de Wang (0,05 éq.) prégonflée dans la diméthylformamide. Après 24 à 72 heures d'agitation à température ambiante, la résine est filtrée puis lavée plusieurs fois avec de la diméthylformamide, du tétrahydrofurane, du diéthyléther et du dichlorométhane. B lb) Preparation of the Piperidone Carbamate Resin It is carried out according to the following scheme

Hydrochloride hydrate piperidone diluted in dimethylformamide is added triethylamine (1 eq.) And molecular sieve. The mixture is heated until complete dissolution of the ketone. This solution is added to the Wang p-nitrophenyl carbonate resin (0.05 eq) pre-swollen in dimethylformamide. After stirring for 24 to 72 hours at room temperature, the resin is filtered and then washed several times with dimethylformamide, tetrahydrofuran, diethyl ether and dichloromethane.

Preparation 2 2.5 g of the p-nitrophenyl carbonate resin of Wang (loading rate of 0.88 mmol / g, 2.2 mmol) is pre-swollen in 100 ml of dimethylformamide. At the same time, 6.7 g (44 mmol, 20 eq) of hydrated piperidone hydrochloride, 4.45 g (44 mmol, 20 eq) of triethylamine and three molecular sieve spatulas are heated in 100 ml of dimethylformamide. until complete dissolution. The yellowish solution is poured hot on the resin and the mixture stirred for 40 hours at room temperature. The resin is filtered and then washed with dimethylformamide, tetrahydrofuran, diethyl ether and dichloromethane (3 times each solvent) and then dried under vacuum. 2.4 g of pale yellow resin are isolated with a loading rate of 0.88 mmol / g calculated from the elemental analysis of nitrogen.

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La procédure générale est la suivante : à la résine cétonique prégonflée dans le triméthylorthoformiate (TMOF) est ajoutée l'amine primaire (5 à 10 éq. ) puis le mélange est soniqué. On ajoute ensuite le complexe de borane pyridine (8 M, 5 à 10 éq. ) et le mélange est agité 12 à 72 heures. La résine est filtrée, lavée avec des solvants tels que le dichlorométhane, la diméthylformamide et le tétrahydrofurane puis séchée sous vide (Pelter, A.; Rosser, R.M. J. Chem. Soc. Perkin Trans I 1984, 717-720 ; Bomann, M.D. ; Guch,I.C.; DiMare, M. J. Org. Chem. 1995,60, 5995-5996 ; Khan, N.M.; Arumugam, V.; Balasubramanian, S. Tetrahedron Lett. B2) Reductive amination on solid support It is carried out according to the diagram

The general procedure is as follows: to the precontaminated ketone resin in trimethylorthoformate (TMOF) is added the primary amine (5 to 10 eq.) And then the mixture is sonicated. The borane pyridine complex (8 M, 5 to 10 eq.) Is then added and the mixture is stirred for 12 to 72 hours. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran and then dried under vacuum (Pelter, A. Rosser, RMJ Chem Soc Perkin Trans I 1984, 717-720, Bomann, MD, Guch , IC, DiMare, MJ Org Chem 1995, 60, 5995-5996, Khan, NM, Arumugam, V, Balasubramanian, S. Tetrahedron Lett.

1996, 37, 4819-4822).

300 mg (taux de charge de 0,88 mmol/g, 0,27 mmol) de résine cétonique sont prégonflés dans le TMOF. On ajoute ensuite la 4-bromophénéthylamine (540 mg, 420 fil, 2,7 mmol, 10 éq. ) puis le complexe de borane pyridine (8 M, 338 l, 2,7 mmol, 10 éq.). Le mélange est agité 56 heures à température ambiante. La résine est filtrée, rincée successivement avec du dichlorométhane, du diméthylformamide, du tétrahydrofurane et du dichlorométhane puis séchée sous vide. 340 mg de résine jaune pale sont ainsi obtenus avec un taux de charge de 0,81 mmol/g calculé d'après l'analyse élémentaire de l'azote. Preparation 3

300 mg (loading rate of 0.88 mmol / g, 0.27 mmol) of ketone resin are preswollen in the TMOF. 4-Bromophenethylamine (540 mg, 420 μl, 2.7 mmol, 10 eq) is then added, followed by borane pyridine complex (8 M, 338.1.7 mmol, 10 eq). The mixture is stirred for 56 hours at room temperature. The resin is filtered, rinsed successively with dichloromethane, dimethylformamide, tetrahydrofuran and dichloromethane and then dried under vacuum. 340 mg of pale yellow resin are thus obtained with a loading rate of 0.81 mmol / g calculated from the elemental analysis of nitrogen.

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La procédure générale est la suivante : la résine "amine secondaire" est prégonflée dans un solvant tel que le dichlorométhane ou le diméthylformamide avant l'addition d'isocyanate ou d'isothiocyanate (3 à 10 éq. ). Le mélange est agité 1 à 24 heures à température ambiante. La résine est alors filtrée, lavée avec des solvants tels que le dichlorométhane, le diméthylformamide et le tétrahydrofurane puis séchée sous vide. B3) Functionalization B3a) Functionalization with isocyanates or isothiocyanates It is carried out according to the diagram

The general procedure is as follows: the "secondary amine" resin is pre-swollen in a solvent such as dichloromethane or dimethylformamide before the addition of isocyanate or isothiocyanate (3 to 10 eq.). The mixture is stirred for 1 to 24 hours at room temperature. The resin is then filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran and then dried under vacuum.

The cleavage of the resin is carried out in the presence of an equimolar mixture of dichloromethane and trifluoroacetic acid and stirring for 30 minutes to 4 hours. The resin is rinsed with dichloromethane and the filtrate is concentrated in vacuo.

In some cases the filtrate is redissolved in dichloromethane and then desalified with a saturated solution of sodium carbonate. The organic phase is evaporated under vacuum to give the free base.

Example B3a: N- (4-Bromophenethyl) -N- (4-piperidinyl) Urea
N '- [4- (trifluoromethyl) phenyl] (C2H23BrF3N3O, M = 470.3)

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 55 mg (50 μmol) of the resin (see preparation 3) are preswollen in anhydrous dichloromethane. 4-trifluorophenylisocyanate (28 mg, 150 mol, 3 eq.) Is then added and the mixture is stirred overnight. The resin is filtered, rinsed with tetrahydrofuran, dimethylformamide, tetrahydrofuran and then dichloromethane before being dried under vacuum. After stirring for 1.5 hours in the presence of 800 μl of an equimolar mixture of dichloromethane and trifluoroacetic acid. The resin is filtered and rinsed with dichloromethane, the filtrate is concentrated, rediluted in dichloromethane and washed with a saturated solution of sodium bicarbonate. 6 mg of a brown oil (yield = 25%) are thus isolated.

1 H NMR (CD 3 OD, 400 MHz): 7.53 (m, 4H); 7.44 (d, J = 6.8 Hz, 2H); 7.21 (d, J = 8.4Hz, 2H); 4.1 (m, 1H); 3.53 (t, J = 7.2 Hz, 2H); 3.12 (d, J = 12.8 Hz, 2H); 2.89 (t, J = 8Hz, 2H); 2.7 (m, 2H); 1.73 (m, 4H). MS / LC: m / z = 472.2 (M + H).

A series of urea (Y = 0) and thiourea (Y = S) were synthesized according to this procedure. The R1 radicals that can be considered are:

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Les radicaux X1 que l'on peut envisager sont ceux illustrés au point A ci-dessus.

The radicals X1 that can be envisaged are those illustrated in point A above.

Procédure générale : la résine "amine secondaire" est prégonflée dans des solvants comme le dichlorométhane, le diméthylformamide ou le tétrahydrofurane. Puis le chlorure de sulfonyle (5 à 10 éq. ) et la triéthylamine (6 à 12 éq. ) sont ajoutés et le mélange agité de 12 à 24 heures à température ambiante. La résine est filtrée, lavée avec des solvants tels que le dichlorométhane, le diméthylformamide et le tétrahydrofurane, puis séchée sous vide. On agite ensuite la résine de 1 à 4 heures en présence d'un mélange équimolaire de dichlorométhane et d'acide trifluoroacétique. B3b) Functionalization with sulfonyl chlorides It is carried out according to the following scheme

General Procedure: The "secondary amine" resin is pre-swollen in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Then the sulfonyl chloride (5 to 10 eq.) And triethylamine (6 to 12 eq.) Are added and the mixture stirred for 12 to 24 hours at room temperature. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, and then dried under vacuum. The resin is then stirred for 1 to 4 hours in the presence of an equimolar mixture of dichloromethane and trifluoroacetic acid.

The resin is rinsed with dichloromethane and the filtrate is concentrated in vacuo. In some cases the filtrate is redissolved in dichloromethane and then desalified with a saturated solution of sodium carbonate. The organic phase is evaporated under vacuum to give the free base.

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55 mg (50 mol) de résine (voir préparation 3) sont prégonflés dans du dichlorométhane anhydre. On ajoute ensuite la triéthylamine (42 l, 300 mol, 6 éq.) puis le chlorure de 4-méthoxybenzène sulfonyle (51,5 mg, 250 mol, 5 éq. ) et le tout est agité toute la nuit. La résine est filtrée, rincée au tétrahydrofurane, au diméthylformamide, au tétrahydrofurane puis au dichlorométhane avant d'être séchée sous vide. On répète la réaction une seconde fois pour avoir une substitution complète. On ajoute 800 l d'un mélange équimolaire de dichlorométhane et d'acide trifluoroacétique et on agite 1,5 heure à température ambiante. La résine est filtrée et rincée au dichlorométhane. Le filtrat est concentré, redilué dans du dichlorométhane et lavé avec une solution saturée de bicarbonate de sodium. 14 mg d'une huile brune (rdt = 63%) ont ainsi été isolés. Example B3b: N- (4-Bromophenethyl) -4-methoxy-N- (4-piperidinyl) phenyl sulfonamide (C20H25BrN2O3S, M = 453.4)

55 mg (50 mol) of resin (see preparation 3) are preswolled in anhydrous dichloromethane. Triethylamine (42 l, 300 mol, 6 eq) is then added followed by 4-methoxybenzenesulphonyl chloride (51.5 mg, 250 mol, 5 eq) and the mixture is stirred overnight. The resin is filtered, rinsed with tetrahydrofuran, dimethylformamide, tetrahydrofuran and then dichloromethane before being dried under vacuum. The reaction is repeated a second time to have a complete substitution. 800 l of an equimolar mixture of dichloromethane and trifluoroacetic acid are added and the mixture is stirred for 1.5 hours at room temperature. The resin is filtered and rinsed with dichloromethane. The filtrate is concentrated, rediluted in dichloromethane and washed with saturated sodium bicarbonate solution. 14 mg of a brown oil (rdt = 63%) were thus isolated.

 1 H NMR (CD 3 OD, 400 MHz) δ: 7.8 (dd, J = 2.8 and 10 Hz, 2H); 7.44 (dd, J = 1.2 and 6.8 Hz, 2H); 7.17 (d, J = 8.4 Hz, 2H); 7.07 (dd, J = 3.2 and 10Hz, 2H); 3.87 (s, 3H, OCH 3); 3.72 (m, 1H); 3.3 (m, 2H); 3.04 (d, J = 12.8 Hz, 2H); 2.92 (t, J = 8.4Hz, 2H); 2.6 (t, J = 12.4Hz, 2H); 1.58 (m, 2H); 1.47 (broad d, J = 10 Hz, 2H). MS / LC: m / z = 455 (M + H).

A series of sulfonamides was synthesized according to this procedure. The radicals RI that can be envisaged are those illustrated at points A and B3a above. The radicals X3 that can be considered are:

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Procédure générale : la résine "amine secondaire" est prégonflée dans des solvants comme le dichlorométhane, le diméthylformamide ou le tétrahydrofurane. Puis le chlorure d'acide (5 à 10 éq. ) et la triéthylamine (6 à 12 éq. ) sont ajoutés et le mélange agité de 12 à 24 heures à température ambiante. La résine est filtrée, lavée avec des solvants tels que le dichlorométhane, le diméthylformamide et le tétrahydrofurane, puis séchée sous vide. On agite ensuite la résine de 1 à 4 heures en présence d'un mélange équimolaire de dichlorométhane et d'acide trifluoroacétique. La résine est rincée au dichlorométhane puis le filtrat est concentré sous vide. Dans certains cas le filtrat est redissout dans du dichlorométhane puis désalifié avec une solution saturée de carbonate de sodium. La phase organique est évaporée sous vide pour donner la base libre. B3c) Functionalization with acid chlorides It is carried out according to the following diagram

General Procedure: The "secondary amine" resin is pre-swollen in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Then the acid chloride (5 to 10 eq) and the triethylamine (6 to 12 eq.) Are added and the mixture stirred for 12 to 24 hours at room temperature. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, and then dried under vacuum. The resin is then stirred for 1 to 4 hours in the presence of an equimolar mixture of dichloromethane and trifluoroacetic acid. The resin is rinsed with dichloromethane and the filtrate is concentrated in vacuo. In some cases the filtrate is redissolved in dichloromethane and then desalified with a saturated solution of sodium carbonate. The organic phase is evaporated under vacuum to give the free base.

55 mg (50 mol) de la résine (voir préparation 3) sont prégonflés dans du tétrahydrofurane anhydre. On ajoute ensuite la triéthylamine (42 /il, 300 mol, 6 éq.) puis le chlorure de 2-thiophène carbonyle (37 mg, 250 mol, 5 éq. ) et le tout est agité toute la nuit. La résine est filtrée, rincée au tétrahydrofurane, au diméthylformamide, au tétrahydrofurane puis au dichlorométhane avant d'être séchée sous vide. On ajoute 800 /il d'un mélange équimolaire de dichlorométhane et d'acide trifluoroacétique et on agite 1,5 heure à température ambiante. La résine est filtrée et rincée au Example B3c: N- (4-Bromophenethyl) -N- (4-piperidinyl) carboxamide
2-thiophene (C18H21BrN2OS, M = 393.3)

55 mg (50 mol) of the resin (see preparation 3) are pre-swelled in anhydrous tetrahydrofuran. Triethylamine (42 μl, 300 mol, 6 equiv) is then added followed by 2-thiophene carbonyl chloride (37 mg, 250 mol, 5 eq) and the mixture is stirred overnight. The resin is filtered, rinsed with tetrahydrofuran, dimethylformamide, tetrahydrofuran and then dichloromethane before being dried under vacuum. 800 μl of an equimolar mixture of dichloromethane and trifluoroacetic acid are added and the mixture is stirred for 1.5 hours at room temperature. The resin is filtered and rinsed with

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 dichloromethane. The filtrate is concentrated, rediluted in dichloromethane and washed with saturated sodium bicarbonate solution. to obtain 10 mg of a brown oil (yield = 50%).

1H NMR (CD3 OD, 400MHz) #: 7.64 (dd, J = 0.8 and 4.8Hz, 1H); 7.44 (d, J = 8.4Hz, 2H); 7.36 (d, J = 3.6 Hz, 1H); 7.14 (m, 3H); 4.11 (m, 1H); 3.61 (t, J = 8Hz, 2H); 3.09 (d, J = 12Hz, 2H); 2.92 (m, 2H); 2.54 (m, 2H); 1.82 (m, 2H); 1.7 (m, 2H). MS / LC: m / z = 393.1 (M + H).

A series of amides was synthesized according to this procedure. The groups R, considered are those illustrated at points A and B3a above. Groups X2 are illustrated below.

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Procédure générale : la résine "amine secondaire" est prégonflée dans des solvants comme le dichlorométhane, le diméthylformamide ou le tétrahydrofurane. Puis B3d) Functionalization with carboxylic acids It is carried out according to the procedure described in the literature (Kobayashi, S. Y., J. Comb Chem 1999, 1, 371-372) according to the scheme:

General Procedure: The "secondary amine" resin is pre-swollen in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. Then

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 the carboxylic acid (3 to 5 eq.), benzo-triazol-1-yl-oxytris-pyrrolidino phosphonium hexafluorophosphate (PyBoP, 3 to 5 eq.) and diisopropylethylamine (6 to 10 eq.) are added and the mixture stirred for 24 hours at room temperature. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran, and then dried under vacuum. The resin is then stirred for 1 to 4 hours in the presence of an equimolar mixture of dichloromethane and trifluoroacetic acid. The resin is rinsed with dichloromethane and the filtrate is concentrated in vacuo. In some cases the filtrate is redissolved in dichloromethane and then desalified with a saturated solution of sodium carbonate. The organic phase is evaporated under vacuum to give the free base.

55 mg (50 jumol) de la résine (voir préparation 3) sont prégonflés dans de la diméthylformamide anhydre. On ajoute ensuite l'acide acétique (8,8 mg, 150 mol, 3 éq. ), le PyBoP (76 mg, 150 mol, 3 éq. ) puis la diisopropyléthylamine (38 mg, 300 mol, 6 éq. ) et le tout est agité toute la nuit. La résine est filtrée, rincée au diméthylformamide, au tétrahydrofurane puis au dichlorométhane avant d'être séchée sous vide. On ajoute 800 fil d'un mélange équimolaire de dichlorométhane et d'acide trifluoroacétique et on agite 1,5 heure à température ambiante. La résine est filtrée et rincée au dichlorométhane. Le filtrat est concentré, redilué dans du dichlorométhane et lavé avec une solution saturée de bicarbonate de sodium pour obtenir 11 mg d'une huile brune (rdt = 68 %). Example B3d: N- [2- (4-bromophenyl) ethyl] -N- (4-piperidinyl) acetamide (C15H21BrN2O, M = 325.25)

55 mg (50 μmol) of the resin (see preparation 3) are preswolled in anhydrous dimethylformamide. Acetic acid (8.8 mg, 150 mol, 3 eq.), PyBoP (76 mg, 150 mol, 3 eq.) And then diisopropylethylamine (38 mg, 300 mol, 6 eq.) Are then added. everything is restless all night. The resin is filtered, rinsed with dimethylformamide, tetrahydrofuran and then dichloromethane before being dried under vacuum. 800 μl of an equimolar mixture of dichloromethane and trifluoroacetic acid are added and the mixture is stirred for 1.5 hours at room temperature. The resin is filtered and rinsed with dichloromethane. The filtrate is concentrated, rediluted in dichloromethane and washed with saturated sodium bicarbonate solution to obtain 11 mg of a brown oil (yield = 68%).

1 H NMR (CD3 OD, 400 MHz) δ: 7.44 (m, 2H); 7.20 (m, 2H); 4.05 (m, 1H); 3.45 (m, 2H); 3.10 (m, 2H); 2.83 (m, 2H); 2.64 (m, 2H); 2.13 (s, 3H); 1.73 (m, 4H). SMICL: m / z = 325.2 (M + H).

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A series of amides was synthesized according to this procedure. The groups R1 envisaged are those illustrated at points A and B3a above. Groups X2 are illustrated in A above.

Procédure générale : à la pipéridine sous forme de base libre diluée dans du dichloromethane, est ajouté un isocyanate ou isothiocyanate (1,1 à 1,5 éq.). Le mélange est agité d'une à 18 heures à température ambiante. La résine aminométhyle (0,2 à 1 éq. ) est ajoutée et le mélange à nouveau agité de 2 à 18 heures. Dans certains cas, de la résine échangeuse d'ions telle que IRA68 ou SAX est ajoutée. Les résines sont filtrées et le filtrat concentré. Dans certains cas, le produit est dissout dans du dichlorométhane ou de l'acétate d'éthyle puis filtré sur une catouche de gel de silice ou d'alumine basique (500 mg, Interchim). C) Functionalization of the piperidine part in solution C1) Preparation of piperidine with R3 = -C (Y) NHX, It is carried out according to the scheme

General Procedure: To the piperidine in free base form diluted in dichloromethane is added an isocyanate or isothiocyanate (1.1 to 1.5 eq.). The mixture is stirred for one to 18 hours at room temperature. The aminomethyl resin (0.2 to 1 eq) was added and the mixture stirred again for 2 to 18 hours. In some cases, ion exchange resin such as IRA68 or SAX is added. The resins are filtered and the filtrate concentrated. In some cases, the product is dissolved in dichloromethane or ethyl acetate and then filtered through a silica gel or basic alumina (500 mg, Interchim) catouche.

Example C1: 4 - ((3,3-Diphenylpropyl) {[3- (trifluoromethyl) anilino] carbonyl} amino) -N-phenyl-1-piperidine carboxamide (C35H35F3N4O2, M =
600.68)

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L'urée de N-(3,3-diphénylpropyl)-N-(4-pipéridinyl)-N'-[3-(trifluorométhyl)phényl] (24 mg, 0,05 mmol) est dissoute dans du dichlorométhane. Le phénylisocyanate (9 mg, 0,075 mmol, 1,5 éq. ) est ajouté et le mélange agité pendant 2,5 heures. La résine aminométhyle (0,02 mmol) est ajoutée et la réaction à nouveau agitée toute la nuit. La résine est filtrée, rincée avec du dichlorométhane et le filtrat concentré.

N- (3,3-Diphenylpropyl) -N- (4-piperidinyl) -N '- [3- (trifluoromethyl) phenyl] urea (24 mg, 0.05 mmol) is dissolved in dichloromethane. The phenylisocyanate (9 mg, 0.075 mmol, 1.5 eq) is added and the mixture stirred for 2.5 hours. The aminomethyl resin (0.02 mmol) is added and the reaction stirred again overnight. The resin is filtered, rinsed with dichloromethane and the filtrate concentrated.

The oil obtained is passed through a cartridge of silica gel eluting with an equimolar mixture of heptane and ethyl acetate to obtain after concentration 12 mg (yield = 40%) of a yellow oil.

1 H NMR (CD 3 OD, 400 MHz) δ: 7.72 (s, 1H); 7.58 (d, 1H); 7.44 (m, 1H); 7.38 (m, 2H); 7.29 (m, 12H); (m, 2H); 7.07 (m, 1H); 4.2 (d, J = 12.4Hz, 3H); 3.21 (t, J = 8Hz, 2H); (t, J = 12.4Hz, 2H); 2.38 (q, J = 8Hz, 2H); 1.73 (d, J = 10 Hz, 2H); 1.54 (qd, J = 3.6 and 12Hz, 2H). MS / LC: m / z = 601.4 (M + H).

A series of ureas (Y = 0) and thioureas (Y = S) were synthesized according to this procedure. The groups R 1, X 1 and X 2 that can be envisaged are those illustrated in the above points (A and B3a), A, and (A and B3c) respectively.

C2) Functionalization with carboxylic acids It is carried out according to the following scheme

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Procédure générale: la résine P-EDC (1,3 à 3 éq. ) est prégonflée dans du dichlorométhane anhydre. L'acide carboxylique (1,1 à 2,5 éq. ) est dissout dans un solvant anhydre tel que le dichlorométhane, le diméthylformamide ou le tétrahydrofurane et ajouté à la résine. Ce mélange est agité de 5 à 30 minutes à température ambiante. On ajoute alors à ce mélange la pipéridine 4-aminodisubstituée, sous forme de base libre, en solution dans un solvant anhydre tel que le dichlorométhane, le diméthylformamide ou le tétrahydrofurane et on agite le tout à température ambiante de 1 à 18 heures. Dans certains cas, de la résine échangeuse d'ions telle que IRA68 ou SAX est ajoutée et le mélange agité à nouveau à température ambiante de 1 à 18 heures. Les résines sont filtrées sur fritté, sur cartouche de résine échangeuse d'ions SAX (500 mg, Interchim) ou sur cartouche d'alumine basique (500 mg, Interchim).

General procedure: The P-EDC resin (1.3 to 3 eq.) Is pre-swollen in anhydrous dichloromethane. The carboxylic acid (1.1 to 2.5 eq) is dissolved in an anhydrous solvent such as dichloromethane, dimethylformamide or tetrahydrofuran and added to the resin. This mixture is stirred for 5 to 30 minutes at room temperature. 4-Aminodisubstituted piperidine, in free base form, in solution in an anhydrous solvent such as dichloromethane, dimethylformamide or tetrahydrofuran is then added to this mixture and the mixture is stirred at room temperature for from 1 to 18 hours. In some cases, ion exchange resin such as IRA68 or SAX is added and the mixture stirred again at room temperature for 1 to 18 hours. The resins are sintered, on a SAX ion exchange resin cartridge (500 mg, Interchim) or on a basic alumina cartridge (500 mg, Interchim).

Example C2: Urea of N- (1-acetyl-4-piperidinyl) -N- (3,3-diphenylpropyl) -
N - [3- (trifluoromethyl) phenyl] (C30H32F3N3O2, M = 523.60)

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117 mg (175 mol, 3,5 éq. ) de résine P-EDC est prégonflée dans 1,5 ml de dichlorométhane anhydre. L'acide acétique (7,5 mg, 125 mol, 2,5 éq. ) est ajouté et le mélange agité 10 minutes. Puis l'urée de N-(3,3-diphénylpropyl)-N-(4pipéridinyl)-N'-[3-(trifluorométhyl)phényl] (24,3 mg, 50 mol) est ajoutée à son tour et le mélange agité toute la nuit. La résine est filtrée et le filtrat concentré. L'huile obtenue est passée sur une cartouche de gel de silice en éluant avec un mélange équimolaire d'heptane et d'acétate d'éthyle pour obtenir après concentration 16mg (rdt = 62 %) d'une mousse blanche.

117 mg (175 mol, 3.5 eq) of P-EDC resin is preswolled in 1.5 ml of anhydrous dichloromethane. Acetic acid (7.5 mg, 125 mol, 2.5 eq) is added and the mixture is stirred for 10 minutes. Then N- (3,3-diphenylpropyl) -N- (4-piperidinyl) -N '- [3- (trifluoromethyl) phenyl] urea (24.3 mg, 50 mol) is added in turn and the stirred mixture All night long. The resin is filtered and the filtrate concentrated. The oil obtained is passed through a cartridge of silica gel eluting with an equimolar mixture of heptane and ethyl acetate to obtain after concentration 16 mg (yield = 62%) of a white foam.

1 H NMR (CD 3 OD, 400 MHz) #: 7.71 (s, 1H); 7.58 (d, J = 8.4Hz, 1H); 7.43 (t, J = 8Hz, 1H); 7.28 (m, 9H); 7.17 (m, 2H); 4.56 (dd, J = 2 and 11.2Hz, 1H); 4.17 (m, 1H); 3.96 (t, J = 7.6 Hz, 1H); 3.88 (d, J = 12Hz, 1H); 3.19 (q, J = 4 and 8Hz, 2H); 3.1 (t, J = 12Hz, 1H); 2.58 (t, J = 12Hz, 1H); 2.37 (m, 2H); 2.06 (s, 3H, CH3); 1.72 (t, J = 14.4Hz, 2H); (qd, J = 4 and 12.4 Hz, 2H).

MS / LC: m / z = 524.3 (M + H).

A series of amides was synthesized according to this procedure. The groups R 1, X 1 and X 2 that can be envisaged are those illustrated at the points (A and B3a), A, (A and B3c) respectively.

C3) Functionalization with sulfonyl chlorides

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Procédure générale: la résine morpholinométhyle (Novabiochem, 2 à 3 éq. ) est prégonflée dans des solvants anhydres tels que le dichlorométhane, le diméthylformamide ou le tétrahydrofurane. Le chlorure de sulfonyle (1,1 à 2 éq.) dissout dans des solvants anhydres tels que le dichlorométhane, le diméthylformamide ou le tétrahydrofurane est ajouté, suivi de la pipéridine 4aminodi substituée. Le mélange est agité de 16 à 48 heures. La résine aminométhyle (0,1 à 1,5 éq. ) est ajoutée et la réaction agitée toute la nuit. Dans certains cas, de la résine échangeuse d'ions telle que IRA68 ou SAX est ajoutée et le mélange agité à température ambiante de 1 à 18 heures. Les résines sont filtrées sur fritté, sur cartouche de résine échangeuse d'ions SAX (500 mg, Interchim) ou sur cartouche d'alumine basique (500 mg, Interchim). It is carried out according to the following diagram

General procedure: the morpholinomethyl resin (Novabiochem, 2 to 3 eq.) Is pre-swollen in anhydrous solvents such as dichloromethane, dimethylformamide or tetrahydrofuran. The sulfonyl chloride (1.1 to 2 eq.) Dissolved in anhydrous solvents such as dichloromethane, dimethylformamide or tetrahydrofuran is added, followed by the substituted piperidine 4aminodi. The mixture is stirred for 16 to 48 hours. The aminomethyl resin (0.1 to 1.5 eq) is added and the reaction stirred overnight. In some cases, ion exchange resin such as IRA68 or SAX is added and the mixture is stirred at room temperature for 1 to 18 hours. The resins are sintered, on a SAX ion exchange resin cartridge (500 mg, Interchim) or on a basic alumina cartridge (500 mg, Interchim).

Example C3: Urea of N- (3,3-diphenylpropyl) -N- {1 - [(4-methoxyphenyl) sulfonyl] -
4-piperidinyl) -N'- [3- (trifluoromethyl) phenyl] (C 35 H 36 F 3 N 3 O 4 S,
M = 651.75)

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27,5 mg (100 mol, 2 éq. ) de résine morpholinométhyle est prégonflée dans du tétrahydrofurane anhydre, on ajoute alors le chlorure de 4-méthoxyphénylsulfonyle (15,5 mg, 0,075 mmol, 1,5 éq. ) puis l'urée de N-(3,3-diphénylpropyl)- N-(4-pipéridinyl)-N'-[3-(trifluorométhyl)phényl] (24,3 mg, 0,05 mmol). Le mélange est agité toute la nuit. Les résines aminométhyle (20 mg) et échangeuse d'ions SAX sont ajoutées et le mélange est agité toute la nuit. Les résines sont filtrées et rincées au dichlorométhane. L'huile obtenue après évaporation est passée sur une cartouche de gel de silice (500 mg, Interchim) en éluant avec de l'acétate d'éthyle pour obtenir après concentration 18 mg (rdt = 56 %) d'un solide blanc.

27.5 mg (100 mol, 2 eq.) Of morpholinomethyl resin is pre-swollen in anhydrous tetrahydrofuran, then 4-methoxyphenylsulfonyl chloride (15.5 mg, 0.075 mmol, 1.5 eq.) Is added, followed by urea N- (3,3-diphenylpropyl) -N- (4-piperidinyl) -N '- [3- (trifluoromethyl) phenyl] (24.3 mg, 0.05 mmol). The mixture is stirred all night. The aminomethyl resins (20 mg) and SAX ion exchange resins are added and the mixture is stirred overnight. The resins are filtered and rinsed with dichloromethane. The oil obtained after evaporation is passed through a cartridge of silica gel (500 mg, Interchim) eluting with ethyl acetate to obtain after concentration 18 mg (yield = 56%) of a white solid.

1 H NMR (CD 3 OD, 400 MHz) δ: 7.71 (d, J = 9.2 Hz, 2H); 7.65 (s, 1H); 7.51 (d, 1H); 7.41 (t, J = 7.6 Hz, 1H); 7.29 (m, 9H); 7.20 (m, 2H); (dd, J = 1.6 and 6.8 Hz, 2H); 3.88 (s, 3H, OCH3); 3.77 (d, J = 12.4Hz, 2H); (t, J = 8Hz, 2H); 2.33 (m, 4H); 1.71 (d, J = 10 Hz, 2H); 1.62 (qd, J = 4 and 12Hz, 2H); 1.3 (m, 2H).

MS / LC: m / z = 652.4 (M + H).

A series of sulfonamides was synthesized according to this procedure. The groups R 1, X 1, X 2 and X 3 that can be envisaged are those illustrated at the points (A and B3a), A, (A and B3c) and B3b respectively.

D) Synthesis of solid phase tri-substituted piperidines It is carried out starting from the vinyl sulfone resin (Kroll, FEK, R. D. Tetrahedron Lett 1997, 38, 8573-8576, Brown, ARJ Comb. Chem.

1999, 1, 283-285) according to the following scheme:

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Au chlorhydrate hydraté de pipéridone dilué dans la diméthylformamide est ajoutée de la triéthylamine (1 éq. ). Le mélange est chauffé jusqu'à dissolution complète de la cétone. Cette solution est ajoutée à la résine vinyle sulfone (0,05 éq. ) prégonflée dans la diméthylformamide. Après 24 à 72 heures d'agitation à température ambiante, la résine est filtrée puis lavée plusieurs fois avec de la diméthylformamide, du tétrahydrofurane, du diéthyléther et du dichlorométhane. Dl) Preparation of the resin It is carried out according to the following scheme:

Hydrochloride hydrate piperidone diluted in dimethylformamide is added triethylamine (1 eq.). The mixture is heated until complete dissolution of the ketone. This solution is added to the vinyl sulfone resin (0.05 eq.) Pre-swollen in dimethylformamide. After stirring for 24 to 72 hours at room temperature, the resin is filtered and then washed several times with dimethylformamide, tetrahydrofuran, diethyl ether and dichloromethane.

Preparation 4 1.5 g of the vinyl sulfone resin (Novabiochem, loading rate of 1 mmol / g, 1.5 mmol) is pre-swollen in 50 ml of dimethylformamide. At the same time, 2.3 g (15 mmol, 10 eq) of hydrated piperidone hydrochloride and 1.8 g (15 mmol, 10 eq) of triethylamine are heated in 100 ml of dimethylformamide until complete dissolution. The yellowish solution is poured hot on the resin and the mixture stirred for 24 hours at room temperature. The resin is filtered and then washed with dimethylformamide, tetrahydrofuran, diethyl ether and dichloromethane (3 times each solvent) and then dried under vacuum. 1.7 g of pale yellow resin are isolated with a feed rate of Immol / g calculated from the elemental analysis of nitrogen.

D2) Reductive amination on a solid support It is carried out according to the procedure described in the literature (Pelter, A. Rosser, R.M.

J. Chem. Soc. Perkin Trans 11984, 717-720; Bomann, M.D .; Guch, I.C .; DiMare, M.

 J. Org. Chem. 1995, 60, 5995-5996; Khan, N.M .; V .; Balasubramanian, S. Tetrahedron Lett. 1996, 37, 4819-4822) according to the scheme:

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Procédure générale : A la résine cétonique prégonflée dans le triméthylorthoformiate (TMOF) est ajoutée l'amine primaire (5 à 10 éq. ) puis le mélange est soniqué. On ajoute ensuite le complexe de borane pyridine (8 M, 5 à 10 éq. ) et le mélange est agité 12 à 72 heures. La résine est filtrée, lavée avec des solvants tels que le dichlorométhane, la diméthylformamide, le méthanol et le tétrahydrofurane puis séchée sous vide.

General Procedure: To the precontaminated ketone resin in trimethylorthoformate (TMOF) is added the primary amine (5 to 10 eq.) Then the mixture is sonicated. The borane pyridine complex (8 M, 5 to 10 eq.) Is then added and the mixture is stirred for 12 to 72 hours. The resin is filtered, washed with solvents such as dichloromethane, dimethylformamide, methanol and tetrahydrofuran and then dried under vacuum.

1 g (taux de charge de lmmol/g, lmmol) de résine cétonique sont prégonflés dans le TMOF. On ajoute ensuite la 2-(1-méthyl-1H-indol-3-yl)éthylamine (1,01 g, 10 mmol, 10 éq. ) puis le complexe de borane pyridine (8M, 1,25 ml, 10 mmol, 10 éq. ). Le mélange est agité 48 heures à température ambiante. La résine est filtrée, rincée successivement avec du dichlorométhane, du diméthylformamide, du méthanol, du tétrahydrofurane et du dichlorométhane puis séchée sous vide. 1,05 g de résine jaune pale sont ainsi obtenus avec un taux de charge de 0,91 mmol/g calculé d'après l'analyse élémentaire de l'azote. Preparation 5

1 g (loading rate of lmmol / g, lmmol) of ketone resin are preswollen in the TMOF. 2- (1-Methyl-1H-indol-3-yl) ethylamine (1.01 g, 10 mmol, 10 eq) is then added, followed by borane pyridine complex (8M, 1.25 ml, 10 mmol, 10 eq.). The mixture is stirred for 48 hours at room temperature. The resin is filtered, rinsed successively with dichloromethane, dimethylformamide, methanol, tetrahydrofuran and dichloromethane and then dried under vacuum. 1.05 g of pale yellow resin are thus obtained with a degree of charge of 0.91 mmol / g calculated from the elemental analysis of nitrogen.

D3) Functionalization of secondary amine D3a) Functionalization with isocyanates

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 General procedure: the "secondary amine" resin is pre-swollen in a solvent such as dichloromethane or dimethylformamide before the addition of the isocyanate (3 to 10 eq.). The mixture is stirred for 1 to 24 hours at room temperature. The resin is then filtered, washed with solvents such as dichloromethane, dimethylformamide and tetrahydrofuran and then dried under vacuum.

55 mg (50 mol) de la résine (voir préparation 5) sont prégonflés dans du dichlorométhane anhydre. On ajoute ensuite le 4-trifluorophénylisocyanate (28 mg, 150 mol, 3 éq. ) et le tout est agité 2 heures à température ambiante. La résine est filtrée, rincée au tétrahydrofurane, au diméthylformamide, au tétrahydrofurane puis au dichlorométhane avant d'être séchée sous vide. Preparation 6

55 mg (50 mol) of the resin (see preparation 5) are preswolled in anhydrous dichloromethane. 4-Trifluorophenylisocyanate (28 mg, 150 mol, 3 eq.) Is then added and the whole is stirred for 2 hours at room temperature. The resin is filtered, rinsed with tetrahydrofuran, dimethylformamide, tetrahydrofuran and then dichloromethane before being dried under vacuum.

D3b) Functionalization with sulfonyl chlorides The functionalization procedure is identical to that described in point B3b.

D3c) Functionalization with acid chlorides The functionalization procedure is identical to that described in point B3c.

D3d) Functionalization with carboxylic acids The functionalization procedure is identical to that described in point B3d.

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Procédure générale : La résine disubstituée est gonflée dans des solvants tels que le dichlorométhane, la diméthylformamide ou le tétrahydrofurane puis est ajouté l'halogénure R3X dans lequel R3 a la signification indiquée précédemment et X représente un atome d'halogène (5 éq. ) et le mélange agité toute la nuit à une température comprise entre 20 et 60 C. La résine est filtrée, rincée avec des solvants tels que la diméthylformamide, le tétrahydrofurane, le méthanol et le dichlorométhane puis séchée sous vide. La résine est regonflée dans le dichlorométhane et de la résine échangeuse d'ions basiques (Ouyang, X.; Armstrong, R.W. ; Murphy, M.M. J. Org. Chem. 1998, 63, 1027-1032) est ajoutée. Agiter le tout 48 heures à température ambiante. Les résines sont filtrées, rincées au dichlorométhane et le filtrat concentré sous vide. D4) Cleavage step The cleavage step described below is valid regardless of the functionalization carried out beforehand on the secondary amine:

General Procedure: The disubstituted resin is swollen in solvents such as dichloromethane, dimethylformamide or tetrahydrofuran and then the halide R 3 X is added in which R 3 has the meaning indicated above and X represents a halogen atom (5 eq) and the mixture is stirred overnight at a temperature of between 20 and 60 ° C. The resin is filtered, rinsed with solvents such as dimethylformamide, tetrahydrofuran, methanol and dichloromethane and then dried under vacuum. The resin is re-flushed in dichloromethane and basic ion exchange resin (Ouyang, X. Armstrong, RW, Murphy, MMJ Org Chem 1998, 63, 1027-1032) is added. Stir the whole thing for 48 hours at room temperature. The resins are filtered, rinsed with dichloromethane and the filtrate concentrated in vacuo.

Example D4: Urea of N- [2- (1-methyl-1H-indol-3-yl) ethyl] -N- (1-methyl)
4-piperidinyl) -N '- [4- (trifluoromethyl) phenyl] (C25H29F3N4O)
M = 458.5)

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55 mg (50 mol) de la résine urée sont gonflés dans de la diméthylformamide puis 35 mg (250 mol, 5 éq. ) de iodométhane sont ajoutés et le mélange agité 18 heures à température ambiante. La résine est filtrée, rincée avec de la diméthylformamide, du tétrahydrofurane, du méthanol et du dichlorométhane puis séchée sous vide. La résine est regonflée dans du dichlorométhane puis environ 100 mg de résine amberlite IRA68 sont ajoutés et le mélange agité 48 heures. Les résines sont filtrées, rincées avec du dichlorométhane et le filtrat concentré pour donner 18 mg (rdt = 78 %) d'une huile incolore.

55 mg (50 mol) of the urea resin are swollen in dimethylformamide and then 35 mg (250 mol, 5 eq) of iodomethane are added and the mixture is stirred for 18 hours at room temperature. The resin is filtered, rinsed with dimethylformamide, tetrahydrofuran, methanol and dichloromethane and dried under vacuum. The resin is reinflated in dichloromethane and then about 100 mg of amberlite resin IRA68 are added and the mixture is stirred for 48 hours. The resins are filtered, rinsed with dichloromethane and the filtrate concentrated to give 18 mg (yield = 78%) of a colorless oil.

1 H NMR (CD 3 OD, 400 MHz): 7.65 (m, 2H); 7.40 (m, 2H); 7.31 (m, 1H); 7.20 (t, 1H); 7.10 (m, 1H); 7.06 (m, 2H); 4.04 (m, 1H); 3.68 (s, 3H); 3.60 (t, 2H); 3.04 (t, 2H); 2.94 (m, 2H); 2.29 (s, 3H); 2.14 (m, 2H); 1.91 (m, 2H); (m, 2H). MS / LC: m / z = 459.3 (M + H).

For groups R1, X1, X2 and X3 as illustrated in points A and B above, the R3 groups that can be considered for the synthesis of trisubstituted 4-aminopiperidines according to the procedure above, are as follows :

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L'invention a également pour objet les procédés de préparation des composés 1 selon l'invention, en phase solide ou liquide, tels que décrits précédemment.

The subject of the invention is also the processes for preparing the compounds 1 according to the invention, in solid or liquid phase, as described above.

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Compounds 1 of the present invention possess valuable pharmacological properties. Thus, compounds I of the present invention have been found to have a high affinity for one or more somatostatin receptors. They can be used as non-peptide agonists or non-peptide somatostatin antagonists, selectively or not.

The compounds of the present invention can thus be used in various therapeutic applications. They can advantageously be used to treat the pathological states or diseases as presented above and in which one (or more) of the somatostatin receptors is (are) involved.

In the experimental section, an illustration of the pharmacological properties of the compounds of the invention is given below.

The subject of the present application is also, as medicaments, the products of formula 1 as defined above, as well as the addition salts with pharmaceutically acceptable mineral or organic acids of said products of formula I, as well as the compositions pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above, in combination with a pharmaceutically acceptable carrier.

The pharmaceutical composition may be in the form of a solid, for example, powders, granules, tablets, capsules or suppositories. Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the invention may also be in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as mixtures thereof, in varying proportions, in water, added to pharmaceutically acceptable oils or fats. . Sterile liquid compositions can be used for intramuscular, intraperitoneal or

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 subcutaneous and sterile compositions may also be administered intravenously.

All technical and scientific terms used in this text have the meaning known to those skilled in the art. In addition, all patents (or patent applications) as well as other bibliographic references are incorporated by reference.

Experimental part Other compounds according to the invention obtained according to the procedures of Examples A, B, C and D previously described are summarized in the table below.

The compounds are characterized by their retention time (tr), expressed in minutes, and their molecular peak (M + H +) determined by mass spectroscopy (MS).

For mass spectroscopy, a single quadrupole mass spectrometer (Micromass, Platform model) equipped with an electrospray source is used with a resolution of 0.8 Da at 50% of valley. The conditions for Examples 1 to 778 below are as follows: Cl and C2 conditions Eluent: A: Water + 0.02% trifluoroacetic acid; acetonitrile

<Tb>
<tb> T (min) <SEP> A <SEP>% <SEP> B%
<tb> 0 <SEP> 100 <SEP> 0 <SEP>
<tb> 1 <SEP> 100 <SEP> 0
<tb> 10 <SEP> 15 <SEP> 85
<tb> 12 <SEP> 15 <SEP> 85
<Tb>

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<Tb>
<tb> Condition <SEP> CI <SEP> Condition <SEP> C2
<tb> Flow rate <SEP>: <SEP> 1,1 <SEP> ml / min <SEP> Flow rate <SEP>: <SEP> 1,1 <SEP> ml / min
<tb> Injection <SEP>: <SEP> 5 <SEP> / it <SEP> Injection <SEP>: <SEP> 20 <SEP> Thread
<tb> Temp <SEP>: <SEP> 40 <SEP> C <SEP> Temp <SEP>: <SEP> 40 <SEP> C
<tb> Length <SEP> of waves <SEP> (% <SEP> UV) <SEP>: <SEP> 210 <SEP> nm <SEP> Length <SEP> of waves <SEP> (% <SEP> UV) <SEP>: <SEP> 210 <SEP> nm
<tb><SEP> Column: <SEP> Uptisphere <SEP> ODS <SEP> 3 <SEP> m <SEP><SEP> Column: <SEP> Kromasyl <SEP> ODS <SEP> 3.5 <SEP> m
<tb> 33 <SEP> * <SEP> 4,6 <SEP> mm <SEP> id <SEP> 50 <SEP> * <SEP> 4,6 <SEP> mm <SEP> id
<Tb>
Conditions C3 Eluent: A: Water + 0.02% trifluoroacetic acid; acetonitrile

<Tb>
<tb> T <SEP> (min) <SEP> A <SEP>% <SEP> B <SEP>% <SEP>
<tb> 0 <SEP> 90 <SEP> 10
<tb> 6 <SEP> 15 <SEP> 85
<tb> 10 <SEP> 15 <SEP> 85
<Tb>
Flow rate: 1 ml / min Injection: 5 l Column: Uptisphere ODS 3 m 50 * 4.6 mm id Temp: 40 C Wavelength (% UV): 220 nm The conditions following the examples, are as follows:

<Tb>
<tb> Examples <SEP> Conditions
<tb> 1 <SEP> to <SEP> 29 <SEP> C2
<tb> 30 <SEP> to <SEP> 263 <SEP> C1
<tb> 264 <SEP> to <SEP> 425 <SEP> C3 <SEP>
<tb> 426 <SEP> to <SEP> 456 <SEP> C2
<tb> 457 <SEP> to <SEP> 503 <SEP> C3
<tb> 504 <SEP> to <SEP> 586 <SEP> C1
<tb> 587 <SEP> to <SEP> 778 <SEP> C3
<Tb>

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 These examples are presented to illustrate the above procedures and should in no way be construed as limiting the scope of the invention. The symbol -> * corresponds to the point of attachment of the radical.

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Ex Rt R2 R3 Purity tr M + H + in% I 0 W sO 66 7,6 523,3 / "'ONI1 / 1" *' * 0 ~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~ * 9 94 7.7 543.2 fl 0 Il 0 96 8 "557,2 ~~~~~~~~~~~~~~~~~ ~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~ 6 ~~~~ 6 l -n c-0 97 8.1 623.1 rVBr 7 "" ## rro2 s 0 95 8.1 588.2 0 8 ".. 0 19 8.1 535.2 F3C "S-% 9" "No2 ~ 0 99 8.5 622.2" "N b- 0 99 85 6222 10 ^ 6CF3 o 80 8,4 611,2 IÍ S" "", ---- "Il ' '## OL ,, 0 99 8.2 569.2 0 * 12 ".. No2 0 93 8.9 656.2 F3C IÍ 13" /, <0 85 9.1 697.0 Br ## - S- his ~~~~~~~~~~ 14 "" - O 95 8,7 611,2 F3C *

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15 ., /=\~ /0 87 7,8 573,2 \ / 5ô * 16 " ^ B 0 100 8,4 653,2 ~~~~~~~~~~~~~~~~~~0#~~~~~~~~~~~~~~~~~~~~~ 17 ci 0 97 8,6 611,1 ci 1 g g 0 99 8,7 636,3 enz N \ 83 7,2 621,2 ~~~~~~~~~~~~~~~~~~~~~~~~" s 0 20 //0 98 7,4 595,2 "T"0* N7, N 21 ^ / \ N 84 7,4 536,3 0 22 ## * r0 99 8,4 614,3 23 ~ / \ N 63 8,2 570,2 '\#/Y=o *"~~~~~~~~~~~~~~~ 24 ff 92 7,5 572,3 * 25 93 8,4 606,4 26 0- 96 7,4 582,3 *'o=0 -0 ~~~~~ ~~~~~ 27 CI-QN 0 \=O 93 8,1 624,2 CF3 * 28 ~ Br /-\ 93 7,8 602,2 \=/=0

15., / = \ ~ / 0 87 7,8 573,2 \ / 5ô * 16 "^ B 0 100 8,4 653,2 ~~~~~~~~~~~~~~~~~~ 0 # ~~~~~~~~~~~~~~~~~~~~~ 17 ci 0 97 8,6 611,1 ci 1 gg 0 99 8,7 636,3 enz N \ 83 7, 2 621,2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 21 ^ / \ N 84 7.4 536.3 0 22 ## * r0 99 8.4 614.3 23 ~ / \ N 63 8.2 570.2 '\ # / Y = o * "~~~~ ~~~~~~~~~~~ 24 ff 92 7.5 572.3 * 25 93 8.4 606.4 26 0- 96 7.4 582.3 * o = 0 -0 ~~~~ ~~~~~~ 27 CI-QN 0 \ = O 93 8.1 624.2 CF3 * 28 ~ Br / - \ 93 7.8 602.2 \ = / = 0

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29 F \ N 95 7,4 585,2 '01=0 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~N0 ."~~~~~~~~~~~ 30 9 87,39 4,0 516,4 31 H 92 5,5 560,3 N 0 32 " " z 1 90 5,7 563,3 w O 33 87,73 5,6 625,4 i p 0 34 85,41 6,0 565,4 * 35 Br 98,4 6,4 671,1 Br / S \ o 36 /\ 0 86 4,9 542,3 Cl 37 w /=\-/ A 89 6,1 572,3 6,1 572,3 38 V f1 77,61 6,8 555,4 39 \ 89,16 4,2 545,4 p " N N 0 40 92,32 5,3 599,3 0 0 41 ci 83 6,0 589,2 Cl 42 /"X 36,3 5,9 531,2

29 F \ N 95 7.4 585.2 '01 = 0 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~ N0. "~~~~ ~~~~~~~ 30 9 87.39 4.0 516.4 31 H 92 5.5 560.3 N 0 32 "" z 1 90 5.7 563.3 w O 33 87.73 5.6 625.4 ip 0 34 85.41 6.0 565.4 * 35 Br 98.4 6.4 671.1 Br / S \ o 36 / \ 0 86 4.9 542.3 Cl 37 w / = \ - / A 89 6.1 572.3 6.1 572.3 38 V f1 77.61 6.8 555.4 39 \ 89.16 4.2 545.4 p "NN 0 40 92.32 5.3 599 , 3 0 0 41 ci 83 6.0 589.2 Cl 42 / "X 36.3 5.9 531.2

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43 " 0-s 83,27 5,9 555,3 / ~~~~~~~~~~~ 44" " W1 82 4,5 564,4 o 1 ::7 1 45" " 86,75 6,0 577,3 46 "O 91,95 4,7 501,4 O/'u1 47 " " 9 88,94 4,5 475,3 * ~~~~~~~~~~ ~~~~ 48" "0 n 0 73 5,3 542,3 -O,N -0 * ~~~~~~ ~~~ ~~~~~ 49 ^ o I 90,96 4,4 486,4 -N+ , 50 " H 95,5 5,9 530,4 N O 51 " 94,51 6,1 533,4 0~~~~~~~~~~~~~~~~~~~~ 52 ## 0 ) 93,64 6,0 595,4 52" / 93,64 6,0 595,4 * 53 " / 96,05 6,5 535,4 * 54 Br 84,68 6,9 641,1 B," 55" "o 86 5,5 512,3 A 56" "c o 92 65 5424 * 57 " 1 fi 91,29 7,2 525,5

43 "0-s 83.27 5.9 555.3 / ~~~~~~~~~~~ 44""W1 82 4.5 564.4 o 1 :: 7 1 45""86.75 6 0 577.3 46 "W 91.95 4.7 501.4 O / 'u1 47""9 88.94 4.5 475.3 * ~~~~~~~~~~~~~~~~~~~~~~ 48 ## EQU1 ## "H 95.5 5.9 530.4 NO 51" 94.51 6.1 533.4 0 ~~~~~~~~~~~~~~~~~~~~ 52 ## 0) 93 , 64 6.0 595.4 52 "/ 93.64 6.0 595.4 * 53" / 96.05 6.5 535.4 * 54 Br 84.68 6.9 641.1 B, "55""o 86 5.5 512.3 A 56""co 92 65 5424 * 57" 1 fi 91.29 7.2 525.5

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58 \ 94,7 4,7 515,4 59 " " \ 94 5,8 569,3 0 ,S.

58, 94.7, 4.7, 515.4, 59.5, 569.3, 0.

60 * VC 89.43 6.6 559.3 ~~~~~~~~~~~ (3 ~~~~~~~~~~~~~ 61 / == \ 32 6.9 501.5 62 "p 93.53 6.4 525.4 63 ^" 94.7 4.9 534.4 lot ,.

64 ## 0 / i 94.32 6.4 547.3 65 / p 91.71 5.2 471.4 0.

66 "92.47 5.0 445.4 * pW ~~~~~~~~~ 67" p 058 5.9 512.3 N 0 ~ 68 - O-> ~ 7 i j? 84.55 5.6 559.4 ~~~~~~~~~~~~~~~~~~~~~ 69 "87.7 4.7 603.4 ~~~~~~~ 3 70 ## ## * / 90.77 4.8 606.4 71 "0) 72.34 4.8 668.4 I 72 87.18 5.1 608.4 o"

<Desc / Clms Page number 90>

73 Br 69,52 5,4 714,1 7 1 0 74 0 63,39 4,2 585,3 ci 75"" w N \-/ 1 54,46 5,1 615,4 76 " " * 1 r1 87,3 5,7 598,4 77 ## * 96,1 3,8 588,4 p o N.N/ 78 - \ 89,9 4,5 642,3 ~~~~~~~~~~~~~~~~~~~~~~~~~ 0 0 79 * C1"V 61,5 5,1 632,3 CI 80 " /=\ 43,65 5,0 574,3 81 o 88,18 5,0 598,3 ~~~~~~~~~~~ g2 ^ 88,6 4,0 607,4 / I N ~~~~~~~~~u~~~ 83 " " 0 90,08 5,1 620,3 84 ## , /\ O 85,57 4,0 544,3 o g5 p 0 48,41 4,5 585,3 -OIN 0 g6 0 82,68 6,1 589,3 o--'' p3C \ / 0 F,C 1 87 ## ## i 79,99 6,5 611,4

73 Br 69.52 5.4 714.1 7 1 0 74 0 63.39 4.2 585.3 ci 75 "" w N \ - / 1 54.46 5.1 615.4 76 "" * 1 r1 87.3 5.7 598.4 77 ## * 96.1 3.8 588.4 in NN / 78 - \ 89.9 4.5 642.3 ~~~~~~~~~~~~~ ## EQU1 ## 0 598.3 ~~~~~~~~~~~~~~~ g2 ^ 88.6 4.0 607.4 / IN ~~~~~~~~~~~~~~~~~~ 90.08 5, 1,620.3 84 ##, / O 85,57 4,0 544.3 o g5 p 0 48,41 4,5 585.3 -OIN 0 g6 0 82.68 6.1 589.3 o-- '' p3C \ / 0 F, C 1 87 ## ## i 79.99 6.5 611.4

<Desc / Clms Page number 91>

88 0 86,07 4,8 503,4 g9 ^ * 82 5,1 551,4 HO 0 90 19,44 4,4 502,4 NH2 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~" 0 91 ## 70 86,48 5,1 550,4 N \\ 92 /X ," 80 6,3 567,3 0 93 N ,O, \-/ / 94,62 6,6 559,3 F3C * 94 - 57"O1 6,9 581,4 !.OH '4737' * jOH 5,2 473,4 /=\ 7~ 87,4 5,6 521,4 0 *y 20,99 5,0 472,4 NH2 0 /=\ 0 88,63 5,7 520,4 98 V-7 * 84 6,7 537,3 99 x # ' N # .

88 0 86.07 4.8 503.4 g9 ^ * 82 5.1 551.4 HO 0 90 19.44 4.4 502.4 NH2 ~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~ "0 91 ## 70 86.48 5.1 550.4 N \\ 92 / X," 80 6.3 567.3 0 93 N, O, \ - / / 94.62 6.6 559.3 F3C * 94 - 57 "O1 6.9 581.4! .OH '4737' * jOH 5.2 473.4 / = \ 7 ~ 87.4 5.6 521 , 4.05, 5.07, 472.4, NH2 0, 88.63, 5.7, 520.4, 98.7, 73.7, 737, 737, 997, 99.75.

0 /, 0 89.71 5.2 632.3 100 NNg F3C> R, 90.25 5.5 654.4 101 0

<Desc / Clms Page number 92>

102" I \* pH 90,09 4,0 546,4 102 * H -0-Lt* 71 4,4 594,3 HO / 103 '#' '# 0 * 37,19 3,8 545,3 104 Il " 0 76,55 4,5 593,4 105 bzz 105 Il w N * 106 -ON N il 0 0 1 69,62 5,9 405,2 106 \-n- * o< \ N 98 7,1 493,2 107 -nN N '≥=1 ;=0 7,1 493,2 107 S/ F3C * * t P N 80 6,0 467,3 108 6,0 467,3 108 --V p 0 1r 88 6,5 471,2 109 'nN N > 6,5 471,2 109 \-N ;=0 0 0 60,04 5,7 427,3 110 ,N'-../'" N I * 111 */NJ p F3C / \ * O N " 78 6,5 515,2 111 \/"-N\/ =/ *A ≥0 FC * t 0- 97 6,2 455,2 112 * T , . N / p 6,2 455,2 #O * ;=0 /#\ 70 5,7 489,3 113 * ,N'-../'" r? P -;=0 N 5,7 489,3 113 ' 0 * J S / 90 6,2 493,3 114 \\/N\y \#/ =0

102 "I * pH 90.09 4.0 546.4 102 * H -0-Lt * 71 4.4 594.3 HO / 103 '#''# 0 * 37.19 3.8 545.3 104 It "0 76.55 4.5 593.4 105 bzz 105 It w N * 106 -ON N il 0 0 1 69.62 5.9 405.2 106 \ -n- * o <\ N 98 7.1 493.2 107 -nN N '≥ = 1; = 0 7.1 493.2 107 S / F3C * * t PN 80 6.0 467.3 108 6.0 467.3 108 --V p 0 1r 88 6.5 471.2 109 'nN N> 6.5 471.2 109 \ -N; = 0 0 0 60.04 5.7 427.3 110, N' - .. / '"NI * 111 * / NJ p F3C / \ * ON "78 6.5 515.2 111 \ /" - N \ / = / * A ≥0 FC * t 0- 97 6.2 455.2 112 * T, N / p 6 , 2,455.2 # O *; = 0 / # \ 70 5.7 489.3 113 *, N '- .. /'"r? P -; = 0 N 5.7 489.3 113 '0 * JS / 90 6.2 493.3 114 \\ / N \ y \ # / = 0

<Desc / Clms Page number 93>

115 * / 62,88 3,6 305,3 115 ,,) N 1'782.99 7' 393,2 tri ( VN 82,99 4,7 393,2 116 -I- N F3C * O 82,99 4,7 393,2 A ?S /~\ 74'42 5,0 393,1 117 \N ci W * )=0 ï t f \ il k /~~\ Vn 10,53 5,4 367,3 118 N) p 0 119 t z s-f Vn 74,79 4,3 371,2 119 \NJ - )=0 120 i NI1 O 50,14 3,4 327,3 120 ><//\/N\J * p / 70 4,3 415,2 121 * \x\/N\ ' \ -)=0 * .≥0 F3C +A 122 * t NJ 0-)=0 " 84 3,9 355,3 122 !\A J <' 7-N 122 \/\N/ # o \~/ -O * ('0 / N p " 66 3,5 389,3 123 /'\/N\/ \≥ * \ c \ sy~yN iir"i:9~ 393,2 124 * Ils ,p N 94,61 3,9 393,2 124 /N\/ -)=0 #fl ï W 77~5"6lT 125 *. -- , N //N O 52 6,6 550,2 1,"\ 52 6,6 550,2 N 6,6 550,2 126 N-" F3C - " 126 N F3C 127 a N-0 57 6,8 550,1 127 '. ci 6,8 550,1

## EQU2 ## 7 393.2 A / S \ 74'42 5.0 393.1 117 \ N ci W *) = 0 ï tf \ il k / ~~ \ Vn 10.53 5.4 367.3 118 N) p 0 119 tz sf Vn 74.79 4.3 371.2 119 \ NJ -) = 0 120 i NI1 O 50.14 3.4 327.3 120><// \ / N \ J * p / 70 4 , 3 415.2 121 * \ x \ / N \ '\ -) = 0 * .≥0 F3C + A 122 * t NJ 0 -) = 0 "84 3.9 355.3 122! \ AJ <' 7 ## EQU1 ## : 9 ~ 393.2 124 * They, p N 94.61 3.9 393.2 124 / N \ / -) = 0 #fl ï W 77 ~ 5 "6lT 125 *. N, N, 52,65,650.2, 6,6550.2 N 6,6550.2 126 N-F3C-126 N F3C 127a N-0 576, 8,550.1 127, and 6.8 550.1

<Desc / Clms Page number 94>

128 t y 5,6 524,2 0 64 6,1 528,2 -N 6,1 528,2 129 N) )=0 ###\Q0275.4 484,3 130 *,N NI 0 5,4 484,3 131 * ("0 N p " 51 6,2 572,2 131 -- \= .>-0 F3c 132 *. -l' , I N " 73 5,7 512,2 132 -O 133 * J 61 5,4 546,2 133 - -)=0 0 43 5,8 550,2 134 ,N -)=0 135 *. -l' , N O 0 5,3 483,3 0 O rl 49 6,4 571,2 N 6,4 571,2 136 N) F3C '≥1 * ;=0 137 * I , I N o " 63 6,6 571,1 137 N) * )=0 ci 79 5,4 545,2 138 ? 5,4 545,2 138 \"- ;=0 0 'SON 57 5,9 549,2 139 N) - ≥0 5,9 549,2 139 o O 66,58 5,2 505,3 140 *,N N 140 *

128 ty 5.6 524.2 0 64 6.1 528.2 -N 6.1 528.2 129 N)) = 0 ### \ Q0275.4 484.3 130 *, N NI 0 5.4 484 , 3 131 * ("0 N p" 51 6.2 572.2 131 - \ =.> - 0 F3c 132 *. -L ', IN "73 5.7 512.2 132 -O 133 * J 61 5.4 546.2 133 - -) = 0 0 43 5.8 550.2 134, N -) = 0 135 *. -L ', NO 0 5.3 483.3 0 O rl 49 6.4 571 , 2 N 6.4 571.2 136 N) F3C '≥1 *; = 0 137 * I, IN o "63 6,6 571.1 137 N) *) = 0 c 79 5.4 545.2 138 ? 5.4 545.2 138 -> = 0 0 'SOUND 57 5.9 549.2 139 N) - ≥0 5.9 549.2 139 o W 66.58 5.2 505.3 140 *, NN 140 *

<Desc / Clms Page number 95>

141 0 F3C N )=1;=0 * Il 61 6,0 593,2 141 X/\\ FC * , 67 5,5 533,2 142 Us) / \ N 5,5 533,2 142 N -0 - * ;= 0 ' fn I \ ff~- \ )"N 61 5,2 567,3 143 , O/ i?0 5,2 567,3 0 o s N 51 5,6 571,2 144 ,/'./N -;=0 145 , N N * OI * * Ô 56 7,0 457,3 145 U.NJ N>X+ XA * t 0 N 64 8,1 545,2 146 <' 7- 146 N) F3C )=1 * )=0 c / \ N 52 8,3 545,2 147 "N ci - o ï T11 69 74 519,3 148 f P 7,1 519,3 148 N) y0 0 149 0 "s-o 70 7,6 523,3 149 J*J - )=0 p O 63,77 6,7 479,4 150 *,/'./N N 150 /N\y N N 50 7,3 567,3 151 \/\/N\/ F3C N )=1)=0 * 7,3 567,3 152 *. -I , / \ N " 46 7,3 507,3 152 N N 0 7,3 507,3 z0 t- p / 78 6,7 541,3 153 * - ' N O *

141 0 F3C N) = 1; = 0 * Il 61 6.0 593.2 141 X / \\ FC *, 67 5.5 533.2 142 Us) / \ N 5.5 533.2 142 N -0 ## EQU1 ## 5 ## STR2 ## ./N -; = 0 145, NN * OI * * δ 56 7.0 457.3 145 U.NJ N> X + XA * t 0 N 64 8.1 545.2 146 <'7- 146 N) F3C ) = 1 *) = 0 c / \ N 52 8.3 545.2 147 "N ci - o ï T11 69 74 519.3 148 f P 7.1 519.3 148 N) y0 0 149 0" n / a 70 7.6 523.3 149 J * J -) = 0 p O 63.77 6.7 479.4 150 *, / '. / NN 150 / N \ y NN 50 7.3 567.3 151 \ / \ / N / / F3C N) = 1) = 0 * 7.3 567.3 152 *. -I, / \ N "46 7.3 507.3 152 NN 0 7.3 507.3 z0 t-p / 78 6.7 541.3 153 * - 'NO *

<Desc / Clms Page number 96>

ro I f-\ 66 7,0 545,3 154 *o J "S-<' -N 7,0 545,3 154 /\/N\/ =/ ≥0 , OI * l 68 6,0 457,2 155 N //N \-65 7,1 545,2 156 -non F3C i>,01≥=o 7,1 545,2 156 N FsC *I . o A ?S \ 67~TT 545,1 157 ci -Ç,-.,O>-O N 7,3 545,1 157 A * o -I- n N 66 6,1 519,2 158 -ON 6,1 519,2 158 N / * o 0 1f .<r77 523,2 159 ! S-<' -)-N o N 6,6 523,2 159 N V/ +>0 0 0 60,49 5,8 479,3 160 \/v-N\/ bzz ' ,/o I \ / # \ / N 60 6,6 567,3 161 * -\ ' / .≥0 6,6 567,3 F3C 162 * , N 0 69 6,2 507,2 #o 163 */NJ 50 5,8 541,2 163 '\ J= 0 0 164 I i -S-C' '>-N 6,2 545,2 165 -ON 0 0 --'Pl 4,4 466,3 1r745 5,5 554,2 166 -ON F3C N 5,5 554,2 166 - F3C

## STR2 ## wherein: ## STR2 ## 2 155 N // N -65 7.1 545.2 156 -non F3C i>, 01≥ = o 7.1 545.2 156 N FsC * I. O A? S \ 67 ~ TT 545.1 157 US-A-7,354,517 A-1-O-N-N-6,6,5,1 519,2 158 -ON 6,1 519,2 158 N / * o 0 1f. <r77 523.2 159! S- <'-) - N o N 6.6 523.2 159 NV / +> 0 0 0 60.49 5.8 479.3 160 \ / vN \ / bzz', / o I \ / # \ / N 60 6.6 567.3 161 * - \ '/ .≥0 6.6 567.3 F3C 162 *, N 0 69 6.2 507.2 #o 163 * / NJ 50 5. 54,541.2163 = 6,2545.2165 -ON 0 0 - 4,446.6 1r745 5.5 554, 2 166 -ON F3C N 5.5 554.2 166 - F3C

<Desc / Clms Page number 97>

167 * t N C1 / * 65,89 5,7 554,1 167 N 168 N 5 5,4 528,2 168 N) o ''"/64,08 5,0 532,2 169 -ON S4 -N 64,08 5,0 532,2 169 N) ;=0 170 0 0 62,51 4,3 488,3 170 N N 55 5,2 576,3 171 ,N F3C )=/;=0 * F3C * 50,35 4,7 516,3 172 N / N 50,35 4,7 516,3 -o 173 r"p <y''5503- 173 ("0 -19*>O 5,2 550,3 0 174 * V o S / N o 48,63 4,8 554,3 174 *-- -;=0 0 F 53 5>7 459,2 175 tlÀ)1 " N )9 "-.. *,F 1 5,7 459,2 175 0 176 N 49 6,9 547,2 176 N) F3C )=/ * ;==0 ci N 61 7,1 547,1 177 tl!)1 " a- N ≥0 7,1 547,1 177 'I- N CI 0 r.-'2- 178 -nN J=" j 5,9 521,2 178 N) ;=0 0 S4 \-N 65 6.4 525.2 179 tl!)1 * '-S-o - ≥0 6,4 525,2 179 N =0

167 * t N C1 / * 65.89 5.7 554.1 167 N 168 N 5 5.4 528.2 168 N) o ''"/ 64.08 5.0 532.2 169 -ON S4 -N 64.08 5.0 532.2 169 N) = 0 170 0 0 62.51 4.3 488.3 170 NN 55 5.2 576.3 171, N F3C) = /; = 0 * F3C * 50 , 4.7 516.3 172 N / N 50.35 4.7 516.3-o 173 r "p <y '' 5503- 173 (" 0 -19 *> O 5.2 550.3 0 174 * S / N o 48.63 4.8 554.3 174 * - -; = 0 0 F 53 5> 7 459.2 175 tlA) 1 "N) 9" - .. *, F 1 5 , 7,459.2 175 0 176 N 49 6.9 547.2 176 N) F3C) = / *; == 0 ci N 61 7.1 547.1 177 tl!) 1 "a- N ≥0 7, ## EQU1 ## '-So - ≥0 6.4 525.2 179 N = 0

<Desc / Clms Page number 98>

18U * J 0 "''N, 0 88,99 5,6 481,3 180 *,N N 181 * rO r\- N 58 6,4 569,2 181 * - ' F3C * 6,4 569,2 182 * t ) -p≥O " 64 6,0 509,2 182 .J' \ N 182 -O /"-0 /-N63 6,0 547,2 183 *' * lg4 ua ()i;f So 67,83 10,1 516,3 r N 0 II 185. /y,61,66 6,7 525,3 A* N- ')#\ 185 / N 1 / - o '1 --"",,* 61,66 6,7 525>3 186 * o / * 40,48 9,9 537,3 186 * 0 rr 40,48 9,9 537,3 0 """ 0 187 * 0 /-\ * 6,4 546,3 188 0 42,57 7,4 478,4 189 tlÚ' * 29 4,8 487,3 190F.<*55 10,3 499,3 * " """ 0" 1 F 191 * F """ 1 '\ N Û) - --"",,* 19,39 6,7 508,3 \A '1" 192 / ()i;f * 67 11,1 567,3 \Y' 0" 1

U.S. No. 0, 0 88.99 5,6 481.3 180 *, NN 181 * rO - N 58 6.4 569.2 181 * - * F3C * 6.4 569.2 182 * t) -p≥O "64 6.0 509.2 182 .Dr. 182 -O /" - 0 / -N63 6.0 547.2 183 * '* lg4 ua () i; f So 67 , 83, 10.1, 516, 3, 0, 0, 185, 61.66, 6.75, 525, 3, 5, 1, 1, 1, 5, 6 61.66 6.7 525> 3 186 * o / * 40.48 9.9 537.3 186 * 0 rr 40.48 9.9 537.3 0 """0 187 * 0 / - \ * 6, 4 546.3 188 0 42.57 7.4 478.4 189 tlÚ '* 29 4.8 487.3 190F. <* 55 10.3 499.3 * """" 0 "1 F 191 * F"& Numsp & numsp & numsp & numsp & numsp & numsp & numsp & numsp & numsp & numsp & numsp & numsp 19,39 6,7 508,3 \ A '1 "192 / () i; f * 67 11,1 567,3 \ Y'0" 1

<Desc / Clms Page number 99>

193 I \ |\ / \ /TA / 64,73 7,9 576,3 193 w / 1 N -0-) - * 194 I--W . O 92 10,6 586,3 195 '\ 85 7,3 595,3 195 / N-<' T## 7,3 595,3 <JL / =/>-* 196 *, o........;f 96 10,5 607,3 V 8 197 * \ 89,25 7,2 616,3 Y '\="- '0 198 ' -N JL J V 98,24 7,9 548,3 199 : / I \N 94 5,6 557,3 200 F:ç C)1;f * 98 10,8 569,2 * " ::::,.,. LJ o F 201 F / \ /-\ 93,17 7,3 578,2 201 * F:ç \/* 93,17 7,3 578,2 202 * /---x* 97,82 Il,7 637,3 202 " V 97,82 11,7 637,3 203 / '\ 1 N - * 88,11 8,5 646,3

193 I / \ / \ / TA / 64,73 7,9 576,3 193 w / 1 N -0-) - * 194 I - W. O 92 10.6 586.3 195 '\ 85 7.3 595.3 195 / N- <' T ## 7.3 595.3 <JL / = /> - * 196 *, o ..... ......... 96 10.5 607.3 V 8 197 * 89.25 7.2 616.3 Y '\ = 0 - 0 198' -N JL JV 98.24 7.9 548.3 199 : 94.56 557.3 200 F: ç C) 1; f * 98 10.8 569.2 * ";::,.,. LJ o F 201 F / \ / - \ 93.17 7.3 578.2 201 * F: ç \ / * 93.17 7.3 578.2 202 * / --- x * 97.82 It, 7 637.3 202 "V 97.82 11.7 637.3 203 / '1 N - * 88.11 8.5 646.3

<Desc / Clms Page number 100>

2M ,#S- ,,0 73 11,2 690,0 ./ / / Br \ S\- O C1 ci 205 \ 60,44 7,9 699,0 0 206 * o U s 11,1 711,0 0 '207"*\ / \ 72,2 7,8 720,0 Il # '≤-' 0 208 : / N LJ 89,42 8,5 ~2w ; Z \ j-\ 48 6>2 659,0 , % / \ a 6,2 659,0 0 210 F / I * 78,2 11,6 673,0 cr F 211 * F r I \ N /-\ / * n 66,1 7,9 682,0 212 * , / U p h/ * " 78 12,6 739,1 ~2W \ 88,77 9,1 750,0 \JJ' / a 214 / \ 0 D 0 10,6 604,3 F3C 215 \N \ 67 7,5 613,2 7r~\ a N 0

2M, # S- ,, 0 73 11.2 690.0 ./ / / Br \ S \ - O C1 ci 205 \ 60.44 7.9 699.0 0 206 * o U s 11.1 711.0 0 '207 "* 72.2 7.8 720.0 ## EQU1 ## ,% / \ a 6.2 659.0 0 210 F / I * 78.2 11.6 673.0 cr F 211 * F r I \ N / - \ / * n 66.1 7.9 682.0 212 *, / U ph / * "78 12.6 739.1 ~ 2W \ 88.77 9.1 750.0 \ JJ '/ a 214 / \ 0 D 0 10.6 604.3 F3C 215 \ N \ 67 7.5 613.2 7r ~ \ a N 0

<Desc / Clms Page number 101>

216 !*############ * 73 10,5 625,3 216 X/-v0- UlJf* 1 10,5 625,3 T L 0 0 -.o"\.r\83 7,3 634,2 217 7,3 634,2 0 218 fi rr""i 87,32 7,9 566,3 N 219 * tLO' '\N-0-) 79 5,7 575,2 N O 220 * FY) Jf * 10,7 587,2 1 \Y F 221 * ." F:ç '- 1 '\ / N - , -",,* " 78,75 7,4 596,2 ''=''-' 222 / I * 95 11,6 655,3 \ l J 0" 1 223 * '\ / N - -",,* 79 8,6 664,3 224 .lN UlJf* N5- 9,4 614,2 * // 0 N--"- S * 225 '\N 78 6,4 623,2 N O "ï ~Z Z JT ~~ 9,2 635,3 226 X/V-y py# -Y 9,2 635,3 1 "0 227 * ." O'- 1 '\ / -0-) - -",,* 6,1 644,3 I

216! * ############ * 73 10,5 625,3 216 X / -v0- UlJf * 1 10,5 625,3 TL 0 0 -.o "\ r 83 7.3 634.2 217 7.3 634.2 0 218 F "" i 87.32 7.9 566.3 N 219 * TLO '' N-0-) 79 5.7 575.2 NO 220 * FY) Jf * 10.7 587.2 1 \ YF 221 *. " F: ç 1 / / / - - - - 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 1 223 * \ / N - - ",, * 79 8,6 664,3 224 .lN UlJf * N5- 9,4 614,2 * // 0 N -" - S * 225 '\ N 78 6 , 4,623.2 NO.ZZ.RTM. 9.2535.3 226 X / Vy py # -Y 9.2 635.3 1 "0 227 *."## STR5 ##

<Desc / Clms Page number 102>

228 6,7 576,3 228 Cf 0 6,7 576,3 N 229 \N .r\~80 585,2 229 tlÚ' '\N-0--) 4,6 585,2 230 fui * 73 9,5 597,2 * 0" F 231 * F:Ç] , '\ N 66 6,2 606,2 , 1 - * 232 62 10,5 665,3 232 Yt JL 0 10,5 665,3 '233',\ .,81 7,5 674,3 233 \ '\ 1 N - * 7,S 674,3 234 -ua * ,,0 92 8,9 540,3 '3 0 N , s , * o 235 -ua---=: '\N 86 5,6 549,2 <JL \=/' 236 * (* 91 8,7 561,3 Li 237 * o \ 94,51 5,4 570,2 ." O....... 1 1 N - * 238 : / N I ô I * 93,36 6,2 502,3 'N k 239 3,8 5H,3 239 tlÚ' '\N-0--) 3,8 511,3 / / ,a

228 6.7 576.3 228 Cf 0 6.7 576.3 N 229 \ Nrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr , 5,597.2 * 0 "F 231 * F:], '\ N 66 6,2 606,2, 1 - * 232 62 10,5 665,3 232 Yt JL 0 10,5 665,3' 233 7, 674.3 234 -ua *, 0 92 8.9 540.3 '3 0 N, s, * o 235 86,5,649.22 (236) (* 91 8.7561.3 Li 237 * o 94.51 5.4 570.2. " O ....... 1 1 N - * 238: / NI ô I * 93.36 6.2 502.3 'N k 239 3.8 5H, 3 239 tlÚ''\ N-0--) 3.8 511.3 / /, a

<Desc / Clms Page number 103>

240 FN rzzT7] 98,13 9,0 523,3 \ 0 F ~24Ï %\ \ f~\ 82~ 5,4 532.2 241 1 1 /N N Ü) 5,4 532,2 242 ''99 10,1 591,3 * " kJ o 243 * '\ 1 N -0-) - * 94,74 6,8 600,3 244 I / 1 / ()IJf \-/ so /r 0 9,8 596,3 N -0 245 / \ 81 6,6 605,3 ff~\ N \ / # \ N 0 '246"' .*96 '617' 246 Y 9,7 617,3 il 0 7 * O \N 85,68 6,4 626,3 0 "1f*98.65 7,1 558.3 248 f T " 98,65 7,1 558,3 N) 249 ; 'r / N I \ / * " 92 4,8 567,2 '25CTi...'96 70,0' 579,2 \/V LJ p F '25rF,\ .T88,12 588.2 251 * FN '\ N -0-) 88,12 6,5 588,2

240 FN rzzT7] 98.13 9.3 523.3 \ 0 F ~ 241% \ \ f ~ \ 82 ~ 5.4 532.2 241 1 1 / NN Ü) 5.4 532.2 242 ''99 10.1 591.3 * kJ o 243 * '1 N -0-) - * 94.74 6.8 600.3 244 I / 1 / () IJf \ - / so / r 0 9.8 596.3 N -0 245 / \ 81 6.6 605.3 ff ~ \ N \ / # \ N 0 '246 "'. * 96 '617' 246 Y 9.7 617.3 il 0 7 * O \ N 85.68 6.4266.3 0 "1f * 98.65 7.1 558.3 248 f T" 98.65 7.1 558.3 N) 249; ## STR1 ## where: ## STR2 ## -0-) 88.12 6.5 588.2

<Desc / Clms Page number 104>

252 ())Jf * 97 10,9 647,3 \ kJ r 253 \ / z / * " 86 7,8 656,3 * "\ /#\ '##* 254 ,#y/- ' 0 79 10,1 572,2 254 t0 0 o-F 0 79 10,1 572,2 F 255 --^1 \ / \ 79 7,0 581,2 255 # \ N-C ##\, 7,0 581,2 <JL \=/\* NO" 256 * / p / * 71 10,0 593,3 256 * '''l8( ())Jf 1 10,0 593,3 ::::... 0 257 7 \ /-\ 72,74 6,6 602,2 257 ." l8( '-. 1 / N - '1 * 72,74 6,6 602,2 0 258 ; / N I ô I * 79,1 7,4 534,3 N k 259 \ n-c' /T-\ x) # \ 74 4,9 543,2 259 tWI / N / \ / * 4,9 543,2 0 260 F)ÇJ ())Jf 84,17 10,3 555,2 * " ::::... u 0" 1 F 261 F / 76,16 6,7 564,2 \D / - '1 * F 262 Jf* 95 11,1 623,3 \ 8

252 ()) * * * * * * * * * * * * * * * 86 7,8 656,3 * "/ # \ * ## * 254, # y / - 0 79 10 , 1 572.2 254 t0 0 oF 0 79 10.1 572.2 F 255 - ^ 1 \ / \ 79 7.0 581.2 255 # \ NC ## \, 7.0 581.2 <JL \ ## EQU2 ## 256 ## EQU1 # 72.74 6.6 602.2 257. " 18 (N-1 / N-1) 72.74 6.6 602.2 0 258; / NI ô I * 79.1 7.4 534.3 N k 259 \ nc '/ T-x) # \ 74 4.9 543.2 259 tWI / N / \ / * 4.9 543.2 0 260 F) ÇJ ()) Jf 84.17 10.3 555.2 * ":::: ... u 0 "1 F 261 F / 76,16 6,7 564,2 \ D / - '1 * F 262 Jf * 95 11,1 623,3 \ 8

<Desc / Clms Page number 105>

263 \ /f"\~ 78,91 8,0 632,3 263 \kJ '\ 1 N -(0 - .-'JI" 78,91 8,0 632,3 0 264 ci H / * 75,26 5,1 430,2 oa 265 \. 0 90,43 5,0 430,3 0CF3 2 l0 74,93 4,3 452,3 o 1 0 ~~~~ ~~~~ 267 > 79,62 4,9 390,3 *jf 268 J?1 ;if 92,82 5,6 490,4 269 \ 68,87 3,6 421,3 o 0 y N 270 -v-Br 79,07 4,9 440,2 0 271 84,22 3,0 392,3 * N'-""",V 272 \ 67,34 4,9 418,2 273 81,63 4,4 352,3

263 78.91 8.0 632.3 263 \ kJ '\ 1 N - (0 - .-' JI "78.91 8.0 632.3 0 264 ci H / * 75.26 5.1 430.2 oa 265.0 0 90.43 5.0 430.3 0CF3 2 l0 74.93 4.3 452.3 o 1 0 ~~~~~~~~ 267> 79.62 4, 9,390.3 * jf 268 J? 1; if 92.82 5.6 490.4 269 \ 68.87 3.6 421.3 o 0 y N 270 -v-Br 79.07 4.9 440.2 0 271 84.22 3.0 392.3 * N '- """, V 272 \ 67.34 4.9 418.2 273 81.63 4.4 352.3

<Desc / Clms Page number 106>

274 90,11 4,7 342,3 '75"054,36 4,3 438,3 o 276 F3C, /=\ /o81,69 4,9 432,2 O 'If 277 85,62 5,2 382,3 0 27g / 86,19 3,2 377,3 0 279 ci 94,76 4,9 451,2 80"*\99,42 4,7 451,3 I CF3 281 ô 90,55 4,0 473,3 0- 0 0 '282'093,80 4,6 411,3 283 " p I * " 82,71 5,4 511,4 0 284 /' I 90,85 3,4 442,3 YI* N 285 Br 98,65 4,6 461,2

274 90.11 4.7 342.3 '75 "054.36 4.3 438.3 o 276 F3C, / = \ / o81.69 4.9 432.2 O 'If 277 85.62 5.2 382 27g / 86.19 3.2 377.3 0 279 ci 94.76 4.9 451.2 80 "* 99.42 4.7 451.3 I CF3 281 δ 90.55 4.0 473 , 302,093.80, 4,611, 283, 82.71, 5, 511.4, 284, 90.85, 3,444, 2,3, Y, N 285 Br 98.65 4.6 461.2

<Desc / Clms Page number 107>

286 0 98,80 2,8 404,3 * N-......."""U 287 O ~~ 86,02 4,6 439,3 f ~J-J 288 97,47 4,1 373,3 O 289 99,31 4,4 363,3 o 290 \ 45,77 4,1 459,3 o ~~~~~ ~~~~ 291 F3C, /=\ .0 94,07 4,6 453,3 #O\ " 292 95,65 5,0 403,4 o 293 N / 94,30 2,9 398,3 O 294 r 0Cl 80,64 5,9 481,2 V 11 1 1 , o"a 295 OaCF3 98,05 5,7 481,3 CF3 296 94,93 5,0 503,4 " 0 / \ -'≥1 >* 0 0 297 a / 96,81 5,6 441,3 297 " .Jt' O 1 96,81 5,6 441,3

286 0 98.80 2.8 404.3 * N -....... """U 287 O ~~ 86.02 4.6 439.3 f ~ JJ 288 97.47 4.1 373, 3 O 289 99.31 4.4 363.3 o 290 \ 45.77 4.1 459.3 o ~~~~~~~~~ 291 F3C, / = \ .0 94.07 4.6 453, 3 # O \ "292 95.65 5.0 403.4 o 293 N / 94.30 2.9 398.3 O 294 r OCl 80.64 5.9 481.2 V 11 1 1, o" a 295 OaCF3 98.05 5.7 481.3 CF3 296 94.93 5.0 503.4 "0 / \ -'≥1> * 0 0 297 a / 96.81 5.6 441.3 297" .Jt ' O, 96.81 5.6 441.3

<Desc / Clms Page number 108>

298 J?îJf* 95,00 6,3 541,4 299 /' I 95,13 4,2 472,4 O 0 N 3000S2.68 3,2 452,4 N, A 300 * 52,68 3,2 452,4 N NÀN 301 r I BT 98,03 5,6 491,2 -,096.44 3,7 217,9 N \,,,,,, 303 a ~ 97,22 5,6 469,3 ~~~~'0~~~~~~~ 304 96,97 5,2 403,3 305 9 99,05 5,4 393,4 306 " \ \ /a " 32,67 5,1 489,3 o * ~~~~~ ~~~~ 307 F3C,O 84,51 5,6 483,3 O\ * 308 98,44 6,0 433,4 a

95,00 6.3 541.4 299 / I 95.13 4.2 472.4 O 0 N 3000S2.68 3.2 452.4 N, A 300 * 52.68 3.2 452.4 N N / A 301 r I BT 98.03 5.6 491.2 -, 096.44 3.7 217.9 N \ ,,,,,, 303 a ~ 97.22 5.6 469.3 ~~~ ~ '0 ~~~~~~~ 304 96.97 5.2 403.3 305 9 99.05 5.4 393.4 306 "\ \ / a" 32.67 5.1 489.3 o * ~ ~~~~~~~~ 307 F3C, O 84.51 5.6 483.3 O \ * 308 98.44 6.0 433.4 a

<Desc / Clms Page number 109>

309 I ~f~\ 97,78 4,0 428,3 N O 310 *. / 79,54 5,0 460,2 / O \ w I 311 \. 78,59 4,9 460,3 CF3 312 66,24 4,2 482,3 jtz o 1 o 313 0 70,15 4,8 420,3 313 * O 1 70,15 4,8 420,3 314 / * 57,87 5,5 520,4 315 /' ' 71,26 3,6 451,3 315 0 ,,71,26 3,6 451,3 Vx N 316 YBr 81,16 4,8 470,2 0 317 74,96 2,9 413,3 N-...."",,'V 318 53,47 4,8 448,3 '3 319 87,88 4,3 382,3 t 320 91,41 4,6 372,3

309 I ~ f ~ \ 97.78 4.0 428.3 NO 310 *. / 79.54 5.0460.2 / O \ w I 311 \. 78.59 4.9 460.3 CF3 312 66.24 4.2 482.3 jtz o 1 o 313 0 70.15 4.8 420.3 313 * O 1 70.15 4.8 420.3 314 / * 57.87 5.5 520.4 315 / '' 71.26 3.6 451.3 315 0 ,, 71.26 3.6 451.3 Vx N 316 YBr 81.16 4.8 470.2 0 317 74.96 2.9 413.3 No. V 318 53.47 4.8 448.3 3 319 87.88 4.3 382.3 t 320 91.41 4 , 6,372.3

<Desc / Clms Page number 110>

321 p 1,59 5,0 468,3 O1,70 322 F3C 0 77,81 4,8 462,3 \ 77,81 4,8 462,3 323 76,59 5,1 412,3 p -324-#############,f-\~83.35 3,1 407.3 324 N / )* 83,35 3,1 407,3 0 325 * / C * 87,42 5,2 444,2 325 /'Y\ \ !T CHg 87,42 5,2 444,2 V #.,;;:; '\ 1 326 \ 98,89 5,1 444,3 326 I CF3 98,89 5,1 444,3 327 95,68 4,3 466,3 JZ/ )d ) 0 0 "328'"0r97,27 4,9 404,3 328 */ O 1 97,27 4,9 404,3 329 J?1 Jf* 95,73 5,7 504,4 330 () 83,37 3,7 435,3 O 0 y N '."#############0'71,88 3,2 413,3 331 \9 71,88 3,2 413,3 N N' ~N

321 p 1.59 5.0 468.3 O1.70 322 F3C 0 77.81 4.8 462.3 \ 77.81 4.8 462.3 323 76.59 5.1412.3 p -324- #############, f- 83.35 3.1 407.3 324 N /) * 83.35 3.1 407.3 0 325 * / C * 87.42 5.2 444 , 2,325; CH: 87.42; 5.2444.2 V #.,;; 1,496 98,89 5.1 444.3 326 I CF3 98.89 5.1 444.3 327 95.68 4.3 466.3 JZ /) d) 0 0 "328" 0r97.27 4.9 404.3 328 * / O 1 97.27 4.9 404.3 329 Y * 1 * 95.73 5.7 504.4 330 () 83.37 3.7 435.3 O 0 y N '. "############# 0'71,88 3,2 413,3 331 \ 9 71,88 3,2 413,3 NN' ~ N

<Desc / Clms Page number 111>

332 \ZbT1 98,33 5,0 454,2 333 0 83,73 3,0 397,3 334 0 94,77 5,0 432,3 3 335 95,88 4,5 366,3 0 336 98,9 4,7 356,3 337 0 50,74 4,4 452,3 338 F3CS /=\ 0 95,39 5,0 446,3 339 98,2 5,3 396,3 340 ~/~A~~ 92,35 3,2 391,3 0 341 -\~ /= * / * 90,41 5,1 444,2 /N 1 / CX nez 342 oaCF3 87,41 5,0 444,3 343 1 87,37 4,3 466,3 0 344 0 83,01 4,9 404,3

332 \ ZbT1 98.33 5.0 454.2 333 0 83.73 3.0 397.3 334 0 94.77 5.0 432.3 3 335 95.88 4.5 366.3 0 336 98.9 4.7 356.3 337 0 50.74 4.4 452.3 338 F3CS / = \ 0 95.39 5.0 446.3 339 98.2 5.3 396.3 340 ~ / ~ A ~~ 92 , 3.2 391.3 0 341 - \ ~ / = * / * 90.41 5.1 444.2 / N 1 / CX nose 342 oaCF3 87.41 5.0 444.3 343 1 87.37 4 , 3 466.3 0 344 0 83.01 4.9 404.3

<Desc / Clms Page number 112>

345 I sJy. / 89,47 5,6 504,4 Or" 346-77,55 3,6 435,3 O 0 Vx N 347049,49 2,4 414,3 347 * 49,49 2,4 414,3 N NÀN 348 * / gr 85,63 4,9 454,2 349 0 88,12 2,9 397,3 * N""""",V 350 v w 87,73 4,9 432,3 " 351 84,48 4,4 366,3 T 352 82,03 4,7 356,3 " O 353 F3. Q-1., 82,93 4,9 446,3 * 354 72,6 5,3 396,3 y 355 N * 86,75 3,2 391,3 O

345 I sJy. / 89.47 5.6 504.4 Gold "346-77.55 3.6 435.3 O 0 Vx N 347049.49 2.4 414.3 347 * 49.49 2.4 414.3 N N / A 348 * / gr 85.63 4.9 454.2 349 0 88.12 2.9 397.3 * N """"", V 350 vw 87.73 4.9 432.3" 351 84.48 4, 4,366.3 T 352 82.03 4.7 356.3 "O 353 F3. Q-1., 82.93 4.9 446.3 * 354 72.6 5.3 396.3 and 355 N * 86.75 3.2 391.3 O

<Desc / Clms Page number 113>

356 F / V ci 93,75 4,7 413,1 \ ci F 357 . 1 !) 96,13 4,6 413,2 0≤CF 358 98,3 3,8 435,2 '3\.. z-)=/ 0 0 359 o 96,45 4,5 373,2 * 360 ?yi Jf* 97,9 5,3 473,4 o 361 97,57 3,0 404,3 o 0 y N 362 0 78,0 2,5 383,2 362 * 78,0 2,5 383,2 N NN 363 / I gr 98,96 4,5 423,1 364 93,98 2,4 366,3 * N-......"",,'V 365 0 97,98 4,5 401,2 (0 366 93,33 4,0 335,2

356 F / V 93.75 4.7 413.1 F 357. 1!) 96.13 4.6 413.2 0≤CF 358 98.3 3.8 435.2 '3 \ .. z -) = / 0 0 359 o 96.45 4.5 373.2 * 360 ? yi Jf * 97.9 5.3 473.4 o 361 97.57 3.0 404.3 o 0 y N 362 0 78.0 2.5 383.2 362 * 78.0 2.5 383.2 N N 363 / I gr 98.96 4.5 423.1 364 93.98 2.4 366.3 * N ,, V, 365 0 97.98 4.5 401, 2 (0 366 93.33 4.0 335.2

<Desc / Clms Page number 114>

367 95,73 4,3 325,3 368 ,O 1,21 3,9 421,3 o * .0 369 F3C, 0 88,55 4,6 415,2 370 95,93 4,9 365,3 0 371 / # \ 99,1 2,6 360,2 Na 0 372 0 0CI 90,59 3,4 392,1 N) ci 373 0 93,57 3,3 392,2 \ f 1 374 97,23 2,6 414,2 ",J;L "'≥1 )...-'r p 0 375 JI' O 1 1 93,83 3,1 352,3 376 ?Ç0Jf* 96,81 4,0 452,4 " 0 377 97,7 2,2 383,3 377 "y o 0 ,,97,7 2,2 383,3 y N

367 95.73 4.3 325.3 368, O 1.21 3.9 421.3 o * .0 369 F3C, 0 88.55 4.6 415.2 370 95.93 4.9 365.3 0 371 / # 99.1 2.6 360.2 Na 0 372 0 0CI 90.59 3.4 392.1 N) c 373 0 93.57 3.3 392.2 1 374 97.23 2, 6,414.2 ", J" L "'≥1) ..." 0 375 JI' O 1 1 93.83 3.1 352.3 376? C0Jf * 96.81 4.0 452.4 " 0 377 97.7 2.2 383.3 377 "yo 0 ,, 97.7 2.2 383.3 y N

<Desc / Clms Page number 115>

378 0 53,69 2,3 362,2 " N N' 'N 379 * / gr 97,1 3,1 402,1 380 O 70,3 2,5 345,3 381 ~ 97,59 3,1 380,2 382 86,74 2,4 314,2 383 87,28 2,6 304,3 384 xo 10,27 3,1 400,2 385 F3CN /=\ O 93,38 3,1 394,2 386 88,99 3,4 344,3 387 // # 89,43 2,5 339,3 0 388 s 86,18 4,2 458,3 o 0> H o 389 37,01 3,9 404,3

378 0 53.69 2,3362.2 "NN '' N 379 * / gr 97.1 3.1 402.1 380 O 70.3 2.5 345.3 381 ~ 97.59 3.1 380 2,382 86.74 2.4 314.2 383 87.28 2.6 304.3 384 xo 10.27 3.1 400.2 385 F3CN / = \ O 93.38 3.1 394.2 386 88, 99 3.4 344.3 387 // # 89.43 2.5 339.3 0 388 s 86.18 4.2 458.3 o 0> H o 389 37.01 3.9 404.3

<Desc / Clms Page number 116>

390 57,02 2,7 437,4 ,. 'NN l" 391 r(YN J".-N- 78,70 4,3 441,3 rr 392 F 67,94 4,6 490,3 392 F I \ F 67,94 4,6 490,3 . .""N h F 393 s ci 39,75 4,5 479,3 393 */ S \N I N 39,75 4,5 479,3 394 94,48 2,8 435,4 .NN 395 .y 83,7 3,4 432,3 , N/" 396 (' 96,5 4,7 464,4 ..0 397 0'l' 0 \N N 43,75 4,5 547,3 )=S * 398 !lÁ) n 86,87 3,3 399,3 .-r\ "N \ I ) 399 47,77 2,9 345,3 400 ^ 'N ,N,N' 82 3,4 382,3 n ÎI rl u s iIN 401 F 97,10 3,8 431,2 401 S F I \ F 97,10 3,8 431,2 . .""N h F F

390 57.02 2.7 437.4,. 78.70 4.3 441.3% 392 F 67.94 4.6 490.3 392% F 67.94 4.6 490.3. "N o F 393 s 39,75 4,5 479,3 393 * / S \ NIN 39,75 4,5 479,3 394 94,48 2,8 435.4 .NN 395 .y 83,7 3.4 432.3, N / "396 (96.5 4.7 464.4 ..0 397 0'l '0 \ NN 43.75 4.5 547.3) = S * 398! LÁ) No. 86.87 3.3 399.3. No. 399 47.77 2.9 345.3 400 .mu.m, N, N, 82, 3.4, 382.3. 401 F 97.10 3.8 431.2 401 SFI 97.10 3.8 431.2. . "" N h FF

<Desc / Clms Page number 117>

402 s ffa 76,92 3,8 420,2 0 403 * 97,3 2,8 373,3 404 s 95,9 4,0 405,3 * N \ 405 0 N 69,50 3,7 488,3 ~~~~0".~~~~~~~ 406 F / S 90,79 4,1 420,3 ! 0 \ \\%% I I F 407 */ S 'NN 86,38 2,5 399,3 408 F 67,52 4,6 452,2 FyyF s Fe F "409 S [N 99,8 2,7 397,3 410 * ~ 97,7 3,3 394,3 N 411 \, ? 87,97 5,0 488,3 412 S 97,23 3,6 467,4 413 99,29 3,7 465,4

402 s ffa 76.92 3.8 420.2 0 403 * 97.3 2.8 373.3 404 s 95.9 4.0 405.3 * N \ 405 0 N 69.50 3.7 488.3 ~~~~ 0 ". ~~~~~~~ 406 F / S 90.79 4.1 420.3! 0 \ \\ %% IIF 407 * / S 'NN 86.38 2.5 399.3 408 F 67.52 4.6 452.2 FyyF s Fe F "409 S [N 99.8 2.7 397.3 410 * ~ 97.7 3.3 394.3 N 411 \,? 87.97 5.0 488.3 412 S 97.23 3.6 467.4 413 99.29 3.7 465.4

<Desc / Clms Page number 118>

414 \. 96,2 4,2 462,4 ii N c::6 415 72,0 5,5 494,3 ..0 416 S 85,09 4,3 467,3 N 417 68,52 4,1 413,3 418 n *IC S 'NN n 98,76 2,8 446,4 419 ^ 'N N +,ri 73,21 4,4 450,3 N //rl//\ 420 F 76,94 4,7 499,2 S FjC( F 421 ci 85>12 4'6 488>2 421 '0 85,12 4,6 488,2 0 422S r) 98,15 2,9 444,4 423 * . 58 5,1 477,3 " N " 424 25 3,6 410,3 ~425 O-'l/~~\~ 69'9 4,6 556,3 ~~~~0".~~~~~~~

414 \. 96.2 4.2 462.4 ii N C :: 6 415 72.0 5.5 494.3 ..0 416 S 85.09 4.3 467.3 N 417 68.52 4.1 413.3 418 n * IC S 'NN n 98.76 2.8 446.4 419 ± NN +, ri 73.21 4.4 450.3 N // rl // \ 420 F 76.94 4.7 499, 2 F F (F 421 C 85> 12 46 488> 2,421 '0 85,12 4,6 488.2 0 422S r) 98.15 2.9 444.4 423 *. 58 5.1 477.3 "N" 424 25 3.6 410.3 ~ 425 O-1 / ~~ 69'9 4.6 556.3 ~~~~ 0 ". ~~~~~ ~~

<Desc / Clms Page number 119>

426 -0-\...o 90,11 8,2 556,3 426 \X) 1 \=:1 ) * 0 427 0 95,30 9,7 552,3 ~~~'0~~~~~~ 428 o 89,35 9,6 573,3 ? 0 429 I * 97,48 11,8 547,4 V o 430 / I 91,35 9,6 591,3 0-S O 0 431 66,60 9,7 557,3 bzz.

426 -0 - \ ... o 90,11 8.2 556.3 426 \ X) 1 \ =: 1) * 0 427 0 95.30 9.7 552.3 ~~~ '0 ~~~~ ~~ 428 o 89.35 9.6 573.3? 0 429 I * 97.48 11.8 547.4 V o 430 / I 91.35 9.6 591.3 0-N / A 0 431 66.60 9.7 557.3 bzz.

432 o S 97.25 10.5 547.3 433 p 98.20 10.2 549.3 F \ -4 \ F "434 *, / '... N (' '0 N 88.28 4.7 489.3, ........, .. --.... / / # \ O 435 O 94.30 5.8 485.3 t lv 436 92.92 5.6 506.3 o 1 0 437 I * 95.73 7.1 480.4 V 0 438 0 89.80 5.6 524.3> S. SO o / NNo

<Desc / Clms Page number 120>

439 n~/Z==\~ 69,38 5,6 490,3 440 0 95,21 6,2 480,3 441 0 96,98 6,0 482,3 442 \ \ - H / 85,00 5,4 456,3 \' 443 0'- Z5 94,40 6,5 452,3 444 \ y\ 91,10 6,3 473,3 o7 445 ,/S* 116,60 7,7 447,3 lJ 446 ,\ 92,80 6,3 491,2 0 447 0/=\~'0 85,40 6,3 457,2 #K, 448 0 96,70 6,9 447,2 II 449 /=\ .0 98 6,7 449,2 450 r o /==* 38,17 3,6 385,2 *//NJ ! / 451 / 92,70 3,4 406,2 451 0 O7 92,70 3,4 406,2 452 /-\/\/\X* 89,50 4,7 380,3 I

439 n ~ / Z = 69.38 5.6 490.3 440 0 95.21 6.2 480.3 441 0 96.98 6.0 482.3 442 \ \ - H / 85.00 5 , 456.3 443 0'- Z5 94.40 6.5 452.3 444 \ y \ 91.10 6.3 473.3 o7 445, / S * 116.60 7.7 447.3 lJ 446, 92.80 6.3 491.2 0 447 0 / = 0 85.40 6.3 457.2 #K, 448 0 96.70 6.9 447.2 II 449 / = \. 0 98 6.7 449.2 450 ro / == * 38.17 3.6 385.2 * // NJ! / 451 / 92.70 3.4 406.2 451 0 O7 92.70 3.4 406.2 452 / - \ / \ / \ X * 89.50 4.7 380.3 I

<Desc / Clms Page number 121>

453 86,24 3,4 424,2 0 \O 454 71,20 3,3 390,2 * 455 S 88,60 3,8 380,2 U 456 89,26 3,5 382,2 F F 457 \ 96,55 4,9 445,3 /0 01≥ 0 458 sr 94,46 4,8 455,2 459 95,6 4,7 411,3 CI N 460 F3C0 N 98,1 5,0 461,3 461 -\ 93,31 5,1 419,4 462 / # \ 97,08 4,2 402,3 463 \ 94,61 4,4 395,3 4 \ 97,05 4,9 503,2 465 " \ / / \ N 95,13 5,1 453,4 66 Z /.O- /# i 93,21 4,8 475,3

453 86.24 3.4 424.2 0 \ O 454 71.20 3.3 390.2 * 455 S 88.60 3.8 380.2 U 456 89.26 3.5 382.2 FF 457 \ 96 , 55 4.9 445.3 / 0 01≥0 458 sr 94.46 4.8 455.2 459 95.6 4.7 411.3 CI N 460 F3C0 N 98.1 5.0 461.3 461 - \ 93.31 5.1 419.4 462 / # \ 97.08 4.2 402.3 463 \ 94.61 4.4 395.3 4 \ 97.05 4.9 503.2 465 "\ / / 95,13 5,1 453.4 66 Z /.O- / # i 93.21 4.8 475.3

<Desc / Clms Page number 122>

467 Br \ N 94,08 4,7 485,2 - )=0 468 CI o- - N 93,08 4,6 441,3 * 469 F3CO -o 95,17 4,9 491,3 \#/ )=0 470 . - /#\ Y-N 89,99 5,0 449,4 " 471 -< /, 7-N 92 4,1 432,3 N\=0 472 F o- - N 94,71 4,3 425,3 * 473 1 o- - N 95,3 4,8 533,2 " 474 OOf N 94,13 5,0 483,4 / - N '≥0 475 -y~/ / # \ 95 5,1 459,3 475 1 v F3C N 5,1 459,3 N -)=0 .-1 476 Br- /#\ N '≥0 94,69 5,0 469,2 477 0-C /#\ N 94,44 4,9 425,3 \==-/=0 478 F3CO -o N 98 5,2 475,3 - )=0 * 479 >-0- - N 96,2 5,3 433,4 =/0 480 \ 93 4,4 416,3 N'=/=0

467 Br \ N 94.08 4.7 485.2 -) = 0 468 CI o- - N 93.08 4.6 441.3 * 469 F3CO -o 95.17 4.9 491.3 \ # /) = 0 470. 89.99 5.0 449.4 "471 - </, 7-N 92 4.1 432.3 N = 472 F O N 94.71 4.3 425.3 * 473 1 o- - N 95.3 4.8 533.2 "474 OOf N 94.13 5.0 483.4 / - N '≥0 475 -y ~ / / # \ 95 5.1 459.3 475 F3C N 5.1 459.3 N -) = 0.-1 476 Br- / ### 94.69 494 467.2 477 0-C / 94.44 4, 9,425.3 \ == - / = 0 478 F3CO -o N 98 5.2 475.3 -) = 0 * 479> -0- - N 96.2 5.3 433.4 = / 0 480 \ 93 4,4 416.3 N '= / = 0

<Desc / Clms Page number 123>

481 F-f /T~\ 94,59 4,6 409,3 482 95,22 5,1 517,2 \=/ ?-N =0 483 /VjfX 95>7 5,3 467,4 483 \ - / / \ N 95,7 5,3 467,4 484---. //=\ 94,8 4,6 457,2 4857=86.7 4,5 420,3 485 N, -<7>-N 86,7 4,5 420,3 486 88,5 4,8 447,3 zig* 487 s Bzz* 96,9 5,1 483,4 488 /X 92,3 4,7 505,2 s 489 - # v~/ sr \ / N 65,4 4,9 471,2 -<7N 490 -0-N >cS 62,6 4,7 434,3 t 491 57,9 5,0 461,3 492 S. 94,2 5,3 497,4 &--0

481 Ff / T ~ \ 94.59 4.6 409.3 482 95.22 5.1 517.2 \ = /? -N = 0 483 / VjfX 95> 7 5.3 467.4 483 \ - / / 95.7 5.3 467.4 484 ---. // = \ 94.8 4.6 457.2 4857 = 86.7 4.5 420.3 485 N, - <7> -N 86.7 4.5 420.3 486 88.5 4.8 447.3 zig * 487 s Bzz * 96.9 5.1 483.4 488 / X 92.3 4.7 505.2 s 489 - # v ~ / sr \ / N 65.4 4.9 471.2 - <7N 490 -0-N> cS 62.6 4.7 434.3 t 491 57.9 5.0 461.3 492 S. 94.2 5.3 497.4 & - 0

<Desc / Clms Page number 124>

493 ~/\~ 54,0 5,0 519,2 * 494 54,6 4,8 501,3 1 r Br \ / N f=S" 1 * 495 /'=\ 64,9 4,7 464,3 N3N f=S" * "496 /=\ 70,4 4,9 491,3 F3CN f=S" * 497 N J ')I,.* 96,5 5,2 527,4 * 498 1# /=\ J#N 55,7 4,9 549,2 in ils * 499 J(0 -0- 57,4 5,1 485,3 /) Br / N f=s 500 /\ 59,3 4,9 448,4 N3N f=s" 501 / 53,6 5,2 475,3 F3CN f=s" * 502 S I 97,8 5,4 511,4 503 ~~/==%\ 10 5,2 533,2 I~A~f~N\ +36,87 \\ f +36,87

493 ~ / 54.0 5.0 519.2 * 494 54.6 4.8 501.3 1 r Br / N f = S "1 * 495 / '= \ 64.9 4.7 464, 3 N3N f = S "*" 496 / = \ 70.4 4.9 491.3 F3CN f = S "* 497 NJ ') I,. * 96.5 5.2 527.4 * 498 1 # / = \ J # N 55.7 4.9 549.2 in they * 499 J (0 -0- 57.4 5.1 485.3 /) Br / N f = s 500 / \ 59.3 4.9 448 , 4 N3N f = s "501 / 53.6 5.2 475.3 F3CN f = s" * 502 IF 97.8 5.4 511.4 503 ~~ / ==% \ 10 5.2 533.2 I ~ A ~ f ~ N \ +36,87 \\ f +36,87

<Desc / Clms Page number 125>

504 h Br4 -NH o 96,33 11,2 646,3 504 f rY# V* Bry-NH 96>33 505 ' 92,67 9,4 690,1 ///S 0 o 506 CT=:\~0 41,11 9,5 656,2 -(-'''".

504 h Br4 -NH o 96.33 11.2 646.3 504 frY # V * Bry-NH 96> 33 505 '92.67 9.4 690.1 /// S 0 o 506 CT =: 0 41.11 9.5 656.2 - (- '''".

507 j 97.65 10.1 646.2 0> -s 508 0 96.29 9.9 648.2 509 - \ / * = 90.89 8.5 501.3 509 '3 * N 0 90, 89 8.5 501.3 510> T 61.04 5.8 401.2 511 p / * * I 99.16 10.5 496.4 512 Jf 95.73 7.1 396.3 513 * Ô l S * 66 9.3 496.3 514 f 95.00 8.9 396.2 515 F3o T # 0 i J-j 96.61 9.5 530.3 0 516 H ", 94.05 6.4 430, 3 517 / = \ pi 87 8.6 536.3 # 0

<Desc / Clms Page number 126>

518 H / 91,59 5,6 436,3 '1 " 519 *, 17 t Je 86,84 8,4 522,3 i w * N 0 520 H / * 94,18 5,4 422,3 Il 521 ;f * t Je 99,75 10,4 517,4 522 H I * 96,8 6,8 417,4 Il 523 *\ n t Je 70,34 9,1 517,3 ô * 0 1 r * 93,49 5,8 417,3 H 525 F3C t 1 93,03 9,3 551,3 o 526 / * 97,13 6,1 451,3 H 527 ' l 9 1 74,37 8,4 557,3 -o po ~528 /T * 92,92 5,3 457,3 H Il " 529 F r N o 92,92 8,8 484,3 '/Y *, f * 0 530 H / * 92,68 5,5 384,2 531 ;f * t !98.29 10,8 479,3 V * 0 532 H / * 96,39 7,0 379,3

518 H / 91.59 5.6 436.3 '1 "519 *, 17 t I 86.84 8.4 522.3 iw * N 0 520 H / * 94.18 5.4 422.3 Il 521; f * t I 99.75 10.4 517.4 522 HI * 96.8 6.8 417.4 Il 523 * \ nt I 70.34 9.1 517.3 o * 0 1 r * 93.49 5 , 8,417.3 H 525 F3C t 1 93.03 9.3 551.3 o 526 / * 97.13 6.1 451.3 H 527 'l 9 1 74.37 8.4 557.3 -0 in ~ 528 / T * 92.92 5.3 457.3 H It 529 F r No. 92.92 8.8 484.3 '/ Y *, f * 0 530 H / * 92.68 5.5 384 , 2,531; f * t! 98.29 10.8 479.3 V * 0 532 H / * 96.39 7.0 379.3

<Desc / Clms Page number 127>

533 \ r\ 0 99 9,5 479,2 " 0 S * 0 534 H / * 99,76 6,0 379,2 535 F3C-0-) t 1 99,17 9,7 513,2 o ~~ # # ; ~~~~~#- 536 H 99,74 6,3 413,2 537 \ 0II 68,71 8,7 519,3 0 -0' 0 538 * 90,09 5,4 419,3 " 539 / H o 91,37 9,8 552,3 N zizi 540 " " H I * 95,39 6,6 452,3 541 (* t K 98,71 11,7 547,4 "0 542 H / * 99,02 7,9 447,4 543 * I O 79,38 10,5 547,3 0 * 0 5q H * 95,46 7,1 447,3 il 545 / \ 0 95,3 10,6 581,3 545 F3C-0-) t 1 95,3 10,6 581,3 0 546 H * 95,45 7,3 481,3 Il ~547 \ /=\ ~]~ 9 I 80,92 9,8 587,3 -o 0

533 \ r \ 0 99 9.5 479.2 "0 S * 0 534 H / * 99.76 6.0 379.2 535 F3C-0-) t 1 99.17 6.7 513.2 o ~~ ##; ## EQU5 # 539 / H 91.37 9.8 552.3 N zizi 540 "" HI * 95.39 6.6 452.3 541 (* t K 98.71 11.7 547.4 "0 542 H / * 99 , 02 7.9 447.4 543 * IO 79.38 10.5 547.3 0 * 0 5q H * 95.46 7.1 447.3 il 545 / \ 0 95.3 10.6 581.3 545 F3C-O-) t 1 95.3 10.6 581.3 0 546 H * 95.45 7.3 481.3 Il ~ 547 \ / = \ ~] ~ 9 I 80.92 9.8 587.3 -o 0

<Desc / Clms Page number 128>

548 / * 92,06 6,5 487,3 H ii 549 ru (J1Jf* -0--) 63 7,7 529,4 N 550079 7,1 495,4 551 *\ N 70 6,7 529,3 551 0 S \=./.- 6,7 529,3 o 5520 77 6,3 495,3 * 553 F3C -0-) - -0--) - r .- 61 6,9 563,3 o 554o69 6,5 529,3 * ~55 /=\ 7~ N~A~ 69 6J~ 569,3 555 ' l N 6,1 569,3 -O 0' 556076 5,8 535,3 * 557 * H \ 79 5,9 555,3 I o 5580M 5,6 521,3 559 o hI N * 90,81 7,4 550,4 0 5600 95,6 6,9 516,4 * 561 * I N 80,85 6,4 550,3 o

548 / * 92.06 6.5 487.3 H ii 549 ru (J1Jf * -0--) 63 7.7 529.4 N 550079 7.1 495.4 551 * \ N 70 6.7 529.3 551 0 S \ =. / .- 6.7 529.3 o 5520 77 6.3 495.3 * 553 F3C -0-) - -0--) - r .- 61 6.9 563.3 o 554o69 6.5 529.3 * ~ 55 / = \ 7 ~ N ~ A ~ 69 6J ~ 569.3 555 'l N 6.1 569.3 -O 0' 556076 5.8 535.3 * 557 * H \ 79 5.9 555.3 I o 5580M 5.6 521.3 559 o HI N * 90.81 7.4 550.4 0 5600 95.6 6.9 516.4 * 561 * IN 80.85 6, 4,550.3 o

<Desc / Clms Page number 129>

562 85,8 6,0 516,3 * 563 F3 N \ 92,92 6,6 584,3 o 0 564 97,26 6,3 550,3 565 \ /=\ / f~\ 82,91 5,8 590,3 o 0 566 87,77 5,5 556,3 567 F , V 86 6.0 517,3 \~~~\~J 568 0 83,41 5,7 483,3 * '569'.Y* 95 7,6 512,3 569 \=:J) 7,6 512,3 o 570 94,08 7,1 478,4 * 571 *\ N87.39 6,5 512,3 571 0 S "=/) 87,39 6,5 512,3 o 572 0 90,06 6,1 478,3 573 c-( /r\ )# N- /# )- 85,61 6,8 546,2 o o 574 0 83,51 6,4 512,3 il " 575 \ /=\ l /#\ 78,63 5,9 552,3 0 ff

562 85.8 6.0 516.3 * 563 F3 N \ 92.92 6.6 584.3 o 0 564 97.26 6.3 550.3 565 / = 82.91 5, 8 590.3 o 0 566 87.77 5.5 556.3 567 F, V 86 6.0 517.3 J 568 0 83.41 5.7 483.3 * 569'.Y * 95 7.6 512.3 569 \ =: J) 7.6 512.3 o 570 94.08 7.1 478.4 * 571 * \ N87.39 6.5 512.3 571 0 S "= /) 87.39 6.5 512.3 o 572 0 90.06 6.1 478.3 573 c- (/ r \) # N- / #) - 85.61 6.8 546.2 oo 574 0 83, 51 6.4 512.3 It "575 \ / = \ l \ # \ 78.63 5.9 552.3 0 ff

<Desc / Clms Page number 130>

576 o 79,58 5,6 518,3 Nez-\ 577 1;1 84 7,1 585,3 * ||] .N n# ? .

576 o 79.58 5.6 518.3 Nez- \ 577 1; 1 84 7.1 585.3 * ||] .N n #? .

~ 578 P 91 6.7 551.3 T yY * "\ - \ 89> 59 8.6 580.4 580 97.13 7.9 546.4 It H * 581 N 83 7.6 580.3 82 9 92.05 7.1 546.3 583 F3C 86 7.8 614.3 583 F'c \ = / A. N \ / / "A 7.8 614.3 o 584095.49 7.3 580.3 585 77 7.0 620.3 0 1 - J oz 586o 91.1 6.6 586.4 * 587 / = **, / - v / T * Jf * 95 4.6 435 587 y. # / \ / v-f Vnh "4.6 588 / = \ 90 4.4 391.3

<Desc / Clms Page number 131>

589 o-/~Vn 88 5,1 435,3 ,--! )=0 ' * ri 590 F3C0 N 92 4,9 447,3 I rO " 591 \ \! /-N rD" 20,32 5,1 399,4 Y=o 592 / r >-o-'I 85 5,3 486,3 '\Y 593 /=\ 97 5,1 442,3 \ / NH 0 594 o-/~Vn 92 5,7 486,4 f - .)=0 595 F3C0 - N 79 5,5 498,3 F3CON \#/ =o 596 / 1 j 93,4 4,68 451,29 <'jU * N %-0 597 | 94,9 4,86 425,27 "NU 598 97,9 5,37 475,22 * "NuCl 1 :::,.. CI 599 r"1 97,1 5,20 457,32 599 * )lN 1 1 97,1 5,20 457,32 600 s 95,1 5,10 441,24 "NU

589 o- / ~ Vn 88 5.1 435.3, -! ) = 590 F3C0 N 92 4.9 447.3 I 591 \ -NRD "20.32 5.1 399.4 Y = o 592 / r> -o-85 5.3, 486.3, 593, = 5.15, 442.3%, n = 595, F3C0-N 79, 5 498.3 F3CON \ # / = o 596/1 d 93.4 4.68 451.29 * N% -0 597 | 94.9 4.86 425.27 "NU 598 97.9 5.37 475.22 *" NuCl 1 :::, .. CI 599 r "1 97.1 5.20 457.32 599 *) lN 1 1 97.1 5.20 457.32 600 s 95.1 5.10 441.24 "NU

<Desc / Clms Page number 132>

601 -\ 0- s 91,1 4,61 481,29 /3 -"o 1 602 s 97,5 4,78 455,29 603 s 98,0 5,28 505,22 N / n 604 s 95,4 5,12 487,33 605 s 94,0 5,03 471,27 606 # V~/\ 89,8 4,86 465,29 J N * \N \ i I 607 s 98,2 5,03 439,29 608 97,6 5,53 489,24 r 609 s \ 93,3 5,36 471,34 610 s 91,4 5,27 455,26 611 , V# / /~A 4,9 459,3 611 -- i F 3C -C> N 0 CH3 4,9 459,3 N 612 Br - N O rr 92,95 4,8 469,2

601 - 91 91 4.61 481.29 / 3 - "o 1 602 s 97.5 4.78 455.29 603 s 98.0 5.28 505.22 N / No 604 s 95, 4 5,12 487.33 605 s 94.0 5.03 471.27 606 # V ~ / \ 89.8 4.86 465.29 JN * \ N \ i 607 s 98.2 5.03 439, 29,608 97.6 5.53 489.24 r 609 s 93.3 5.36 471.34 610 s 91.4 5.27 455.26 611, V # / / ~ A 4.9 459.3 611 - F F 3 C -C> N 0 CH 3 4.9 459.3 N 612 Br - NO rr 92.95 4.8 469.2

<Desc / Clms Page number 133>

613 /# \ Vn 91,61 4,7 425,3 ~614 F3co-f IFÂ Vn 92 5,0 475,3 615 \ 85,2 5,1 433,4 616 / \ N 83 4,2 416,3 617 \ 94,11 4,4 409,3 618 \ 93,85 5,0 517,2 619 92'74 5l1 467'4 619 92,74 5,1 467,4 620 FgC - N 91 4,8 489,3 /3 <}- 621 Br N 91,9 4,7 499,3 Br-C \=/=0 622 / \ N 89,71 4,6 455,3 \#/ =0 623 F3CO N 90 4,9 505,3 ~623 F3co- f~\ 'N 4-9 505'3 624 \ 83>96 5,0 463,4 Vn 625 87 4,1 446,3 625 -<' -N 4,1 446,3 626 \ 93,1 4,3 439,3 *

613 / # \ Vn 91.61 4.7 425.3 ~ 614 F3co-f IFn Vn 92 5.0 475.3 615 \ 85.2 5.1 433.4 616 / \ N 83 4.2 416.3 617,94,11 4,4409.3 618 93.85 5,0 517,2 619 92,74 5l1,467'4,619 92.74 5,1 467,4 620 FgC-N 91 4,8489 3/3 <} - 621 Br N 91.9 4.7 499.3 Br-C \ = / = 0 622 / \ N 89.71 4.6 455.3 \ # / = 0 623 F3CO N 90 4, 9 505.3 ~ 623 F3co-f ~ \ 'N 4-9 505'3 624 \ 83> 96 5.0 463.4 Vn 625 87 4.1 446.3 625 - <-N 4.1 446, 3,626 \ 93.1 4.3 439.3 *

<Desc / Clms Page number 134>

627 1 O - 93,21 4,8 547,2 * 628 " \ / / \ N 90,67 5,0 497,4 629 w 79,6 4,9 485,2 . 1 f N .# Br,1N 'rS N 630 /=\ 72,8 4,8 448,3 * 631 /'=\ 78,7 5,1 475,3 F3CN 'rS" 632 S '::110... 97,3 5,4 511,4 N * 633 /=='\ 51,5 5,1 533,2 IN 'rS" * 634 (DO- /=\ 76,1 4,9 515,3 f BrN N 'rS" 635 -0- 74,2 4,7 478,3 N3 \ / N N3 * 636 /==\ 76,5 5,0 505,3 F3c-vJ>-v F3CN S 637 S '::110... 97,7 5,3 541,4 638 /=\ 71,4 5,0 563,2 1 iJ" v *

627 1 O - 93.21 4.8 547.2 * 628 "\ / / \ N 90.67 497.4 629 w 79.6 4.9 485.2.1 n N # Br, 1N N 630 / = 72.8 4.8 448.3 * 631 / '= \ 78.7 5.1 475.3 F3CN' rS "632 S ':: 110 ... 97.3 5.4 511.4 N * 633 / == '51.5 5.1 533.2 IN' rS "* 634 (DO- / = \ 76.1 4.9 515.3 f BRN N 'rS" 635 -0 - 74.2 4.7 478.3 N3 / N N3 * 636 / == 76.5 5.0 505.3 F3c-vJ> -v F3CN S 637 S ':: 110 ... 97.7 5.3 541.4 638 / = \ 71.4 5.0 563.2 1 iJ * v *

<Desc / Clms Page number 135>

639 ""V-/ s 82,54 4,4 451,3 'J -"0:) /O 640S93,42 4,2 397,3 * N 1 O 641 S 98,93 2,9 430,4 j,*' N N (42 S ^ /N3 81,46 4,5 434,3 * N (I 643 F 96,41 4,9 483,3 si fyV ,N'\P F 644 s ci 91,55 4,7 472,3 jf 1 NN0, 645 S 97,96 2,9 428,4 646 *i Il 96,9 5,0 425,3 647 s 95,8 4,9 457,3 */ N 648 \* 91,41 4,6 540,3 N I 0 \ 0 N 91,41 4,6 540,3 ..JU 649 --\ / s 88,0 4,75 465,3 'o 0\ 10 650s 99,0 4,89 439,3 651 98,5 5,42 489,2 N^ / WN c

639 "" V- / s 82.54 4.4 451.3 'J - "0 :) / O 640S93.42 4.2 397.3 * N 1 O 641 S 98.93 2.9 430.4 d NN (42 S) / N3 81.46 4.5 434.3 * N (1643 F 96.41 4.9 483.3 if fyV, N '\ PF 644 s 91.55 4.7 472.3 1 NN0, 645 S 97.96 2.9 428.4 646 * i Il 96.9 5.0 425.3 647 s 95.8 4.9 457.3 * / N 648 \ * 91, 41 4.6 540.3 N 0 0 N 91.41 4.6 540.3 ..JU 649 - \ / s 88.0 4.75 465.3 'o 0 \ 10 650s 99.0 4, 89 439.3 651 98.5 5.42 489.2 N ^ / WN c

<Desc / Clms Page number 136>

652 s 93,3 5,24 471,3 653 s "nez 87,6 5,14 455,3 654 0- s 88,3 4,66 495,3 1 r N 655 98,1 4,82 469,3 656 98,4 5,34 519,2 657 II / 95,4 5,16 501,3 658 s 898 508 485,3 659 ,~\~/\ /r, 80,76 4,84 410,2 #'<xJ a "A-K,,.

652 s 93.3 5.24 471.3 653 s "nose 87.6 5.14 455.3 654 0- s 88.3 4.66 495.3 1 r N 655 98.1 4.82 469.3 656 98.4 5.34 519.2 657 II / 95.4 5.16 501.3 658 s 898 508 485.3 659, ~ \ ~ / \ / r, 80.76 4.84 410.2 # '<xJ a "AK ,,.

660 Yi 61.69 4.97 426.2 661 .Br 90.93 4.79 454.1662 F- / T \ # 91.55 4.58 394.2 663 Br 9199 4gag 454.1

<Desc / Clms Page number 137>

664 F3C ~ * 92,79 5,55 526,2 F,C 665 /f~\ 93,78 5,02 502,1 O 666 96,3 4,75 408,2 0 '# 667 81,2 5,02 408,2 ci 668 #v# Z0" 0 90,79 4,74 440,2 * 1 r // /. - '1 N 669 m 78,93 4,88 456,3 670 Br 91,87 4,69 484,2 \=/\#* 0 671 ~/~~V~ 91,19 4,51 424,2 F )* o 672 BT 95,27 4,79 484,2 O 673 F3C * 89,5 5,46 542,2 F3C )J F,C 674 90,77 4,92 532,1 0 675 95,1 4,66 438,2 F \ / 1 '# Il 676 /=\ * 88,7 4,92 524,2 C "'"c

664 F3C ~ * 92.79 5.55 526.2 F, C 665 / f ~ 93.78 5.02 502.1 O 666 96.3 4.75 408.2 0 '# 667 81.2 5, 02 408.2 ci 668 # v # Z0 "0 90.79 4.74 440.2 * 1 r // /. - '1 N 669 m 78.93 4.88 456.3 670 Br 91.87 4, 69 484.2 \ = / \ # * 0 671 ~ / ~~ V ~ 91.19 4.51 424.2 F) * o 672 BT 95.27 4.79 484.2 O 673 F3C * 89.5 5 , 46,542.2 F3C) JF, C 674 90.77 4.92 532.1 0 675 95.1 4.66 438.2 F / 1 # Il 676 / = \ * 88.7 4.92 524 , 2 C "'" c

<Desc / Clms Page number 138>

677 ~/~~V~ , 81,65 4,99 424,2 IN CI 0 J N O 67g / I ; 70,32 5,11 440,3 67g Br 90,06 4,96 468,2 680 F \ ' 94,11 4,74 408,2 0 681 Br 93,96 5,04 468,2 0 682 Fs * 93,3 5,66 540,2 F3C 683 -\ / * , 94,79 5,16 516,1 0 684 96,5 4,9 422,3 685 88,2 5,19 438,2 <7- 686 /"Y Cl CH3 "Y 87,93 4,86 424,2 686 / N, j -\ CH3 87,93 4,86 424,2 687 / I w 84,74 440,2 6gg Br 95,34 4,82 468,2

677 ~ / ~~ V ~, 81.65 4.99 424.2 IN CI 0 JNO 67g / I; 70.32 5.11 440.3 67g Br 90.06 4.96 468.2 680 F 94.14 4.40 408.2 0 681 Br 93.96 5.04 468.2 0 682 Fs * 93 , 3 5,66 540.2 F3C 683 - \ / *, 94.79 5.16 516.1 0 684 96.5 4.9 422.3 685 88.2 5.19 438.2 <7- 686 / "Y Cl CH3" Y 87.93 4.86 424.2 686 / N, j - \ CH3 87.93 4.86 424.2 687 / I w 84.74 440.2 6gg Br 95.34 4.82 468.2

<Desc / Clms Page number 139>

689 /, 89,78 4,6 408,2 \ / 0 690 Br 95,16 4,9 468,163 f 0 691 Fa ~ * 95,6 5,56 540,2 F3C )J C 692 / \ 95,24 5,05 516,3 \=./ * 0 693 96,6 4,8 422,2 F \ / " '# '.c 694 * 90,4 5,04 438,2 ci " 695 /"h3" a-0--) 93,12 4,78 454,2 '1 N 696 / I w 86,11 4,92 470,3 697 Br 94,89 4,73 498,2 0 698 94,1 4,54 438,3 0 699 Br 95,66 4,81 498,2 0

689 /, 89.78 4.6 408.2 / 0 690 Br 95.16 4.9 468.163 f 0 691 Fa ~ * 95.6 5.56 540.2 F3C) JC 692 / 95.24 5, 05 516.3 \ =. / * 0 693 96.6 4.8 422.2 F / / ''#'.c 694 * 90.4 5.04 438.2 ci "695 /" h3 "a-0 -) 93,12 4,78 454,2 '1 N 696 / I w 86,11 4,92 470.3 697 Br 94.89 4.73 498.2 0 698 94.1 4.54 438.3 0 699 Br 95.66 4.81 498.2 0

<Desc / Clms Page number 140>

700 F3C 94,8 5,48 570,2 F,C O 701 I / \ * 93,63 4,96 546,1 0 ~~ /# n ~ 96,7 4,7 452,3 0 703 * 85,6 4,96 468,2 704 * \ CH3 ~~ O T * 78,36 3,14 359,1 -Q- 1-k0 #0 ~ol * /sCB, ~~ ~ô 47,4 3,9 367,1 705 CHs F3C S o 47,4 3,9 367,1 706 * CH3 /0 69,72 4,28 385,2 0 -Q- 0 #o 707 * CH3 /0 34,86 4,96 393,2 F3C \ S O 7pg F3C \ S 0 * 37,54 4,91 449,2 (P -<D- -\, 0 709 ~ 0 81,57 4,46 483,1 #o 710 /0 O 55,98 5,12 491,1 711 T ,=*. /0 73,74 3,09 441,2 N N-CH, )## 712 /C 40,19 2,85 449,2 \-Y N-CH, -<D- --*> 0 \#N N# CH3 ##

700 F3C 94.8 5.48 570.2 F, CO 701 I / * 93.63 4.96 546.1 0 ~~ # 96.7 4.7 452.3 0 703 * 85.6 4.96 468.2 704 * \ CH3 ~~ OT * 78.36 3.14 359.1 -Q-1-k0 # 0 ~ ol * / sCB, ~~ ~ o 47.4 3.9 367.1 705 CHs F3C S o 47.4 3.9 367.1 706 * CH3 / 0 69.72 4.28 385.2 0 -Q- 0 #o 707 * CH3 / 0 34.86 4.96 393.2 F3C W 0 S F 3 C S 0 37.54 4.91 449.2 (P <0.01, 0 709 81.57 4.46 483.1 # O 710/0 0 55.98 5, 12 491.1 711 T, = *. / 0 73.74 3.09 441.2 N N-CH,) ## 712 / C 40.19 2.85 449.2 \ -Y N-CH, - < D- - *> 0 \ # NN # CH3 ##

<Desc / Clms Page number 141>

713 l -0- 0 90,07 3,18 426,2 o 0 b s--..* 6 0 " 714 1 F3C ~ / o 74,98 3,84 434,2 F3CS* 6 ""\/\ /#\ / 78,14 4,24 397,2 '\J' o b S --..

713 l -0- 0 90.07 3.18 426.2 o 0 b s - .. * 6 0 "714 1 F3C ~ / o 74.98 3.84 434.2 F3CS * 6""\ / \ / # \ / 78,14 4,24 397,2 '\ J' ob S - ..

## EQU1 ## = x ~ δ 37.75 5.01 485.1 ~ -F F3C ~ / S 37.75 5.01 485.1 CF3 719 * CH3 70.3 5.2 412.1 Cl # ('\ # / N ) -N ≥O CI) = / *; = 0 720 CH 3 JI 70.7 5.0 386.1 721 0 61.9 6.3 600.3 '722' / \ 49.3 'T 538.4 722 "0 * N j; P = 0 49.3 6.1 538.4 723i / F, MO 5.1412.2 723." <'≥0 65.0 5.1412.2 Cl) = / * 7U "" CH 3 / 44.3 4.9 386.2

<Desc / Clms Page number 142>

725 0 49,2 6,2 600,3 726A,,37,5 6,0 538,4 726 \ )#N 37,5 6,0 538,4 * 727 /r S7.1 5,t 468,1 727 h j C1~\ // VN X/\. * S"7-1 5,1 468,1 k CI - * ;==0 0 t * 728 f* 84,4 4,9 442,1 CH3 Il Il 729 0 82,3 6,2 656,3 730 N 93,8 4,7 406,3 731 Jf* 80,7 4,6 380,3 CH3 732 0 84,1 5,9 594,3 733 CI -o- 67,9 4,7 462,1 733 .o a-( Vn >-o .. # 67,9 4,7 462,1 "0=0 CI ;=0 0 734 CH3 /" 66,9 4,6 436,1 735 0 56,8 5,9 650,2 736 N '%t/"sA. 88,1 4,3 400,3 * 737 CH3 /" 82,8 4,1 374,3 CH3

725 0 49.2 6.2 600.3 726A ,, 37.5 6.0 538.4 726 \) #N 37.5 6.0 538.4 * 727 / r S7.1 5, t 468.1 727 hd C1 ~ \ // VN X / \. * S "7-1 5.1 468.1 k CI - *; == 0 0 t * 728 f * 84.4 4.9 442.1 CH3 Il Il 729 0 82.3 6.2 656.3 730 N 93.8 4.7 406.3 731 Jf * 80.7 4.6 380.3 CH3 732 0 84.1 5.9 594.3 733 CI -o- 67.9 4.7 462.1 733. o a- (Vn> -o .. # 67.9 4.7 462.1 "0 = 0 CI; = 0 0 734 CH3 /" 66.9 4.6 436.1 735 0 56.8 5.9 650.2736 N '% t / "sA 88.1 4.3 400.3 * 737 CH3 /" 82.8 4.1 374.3 CH3

<Desc / Clms Page number 143>

738 o 51,4 5,6 588,3 739 \<\/v /f~\ 77,7 5,1 446,2 739 Y'" 1 (7 ≥/ VN ≥o 77,7 5,1 446,2 i! a * 74p JI 76,1 4,9 420,2 CH3 741 QYlo 1 67,1 6,2 634,3 !!! I l1 X 742 " N O * 88,9 4,7 384,3 * 743 CH3 JI * 79,3 4,5 358,3 " 744 0 65,1 5,9 572,4 geri 745 l 80,0 4,0 398,3 *CH3 o=>: N 746 CH3 / 76,9 3,8 372,3 3 747 0 42,7 5,8 586,4 748 NOz 0 64,6 4,4 483,3 no2-oX; * 749 t 87,4 5,3 409,3 eGo

738 o 51.4 5.6 588.3 739 \ <\ / v / f ~ \ 77.7 5.1 446.2 739 Y '"1 (7 ≥ / VN ≥o 77.7 5.1 446, JI 76.1 4.9 420.2 CH3 741 QYlo 1 67.1 6.2 634.3 !!! I l1 X 742 "NO * 88.9 4.7 384.3 * 743 CH3 JI * 79.3 4.5 358.3 "744 0 65.1 5.9 572.4 geri 745 l 80.0 4.0 398.3 * CH3 o =>: N 746 CH3 / 76.9 3 , 8,372.3 3,747 0 42.7 5.8 586.4 748 NOz 0 64.6 4.4 483.3 no2-oX; * 749 t 87.4 5.3 409.3 eGo

<Desc / Clms Page number 144>

750 / 71,0 5,1 383,3 CH3 il 751 0 59,8 6,7 597,4 752 " " NOz 0 84,4 5,6 494,3 N0c/, 753 I ' * 80,1 3,9 398,3 # s/ N 754 CH3 3 / 63,1 3,7 372,3 CHg 755 NOz 0 64,4 4,3 483,3 * 756 : 84,6 5,3 409,3 090 757 CH 3 JI 59,6 5,0 383,3 758 QYlo 1 52,9 6,6 597,4 759 NOz 0 81,6 5,5 494,3 * 760 ça"" "" 75,3 5,3 465,3 bzz* 761 CH3 / 60,3 5,1 439,3

750 / 71.0 5.1 383.3 CH3 751 0 59.8 6.7 597.4 752 "" NOz 0 84.4 5.6 494.3 N0c /, 753 I '* 80.1 3, 9,398.3 # s / N 754 CH3 3 / 63,1 3,7 372.3 CHg 755 NOz 0 64.4 4.3 483.3 * 756: 84.6 5.3 409.3 090 757 CH 3 JI 59.6 5.0 383.3 758 QYlo 1 52.9 6.6 597.4 759 NOz 0 81.6 5.5 494.3 * 760 that """" 75.3 5.3 465.3 bzz * 761 CH3 / 60.3 5.1 439.3

<Desc / Clms Page number 145>

762 9 61,8 6,6 653,4 763 ir~\ 74,4 5,6 550,3 763 N02 0 74,4 5,6 550,3 * 764 + l 74,5 3,6 448,2 Y'y ) crP N 765 CH3 ./" 51,3 3,4 422,2 '1 766 " " N02 0 58,8 3,9 533,2 * 767 : 86,2 4,8 459,3 eGo 768 CH3 ./" 63,2 4,6 433,3 769 0 60,1 6,2 647,4 770T83,5 5,1 544,2 770 N02 0 83,5 5,1 544,2 t m <.Y"68,1 4,1 432,3 771 T o 68,1 4,1 432,3 772 CH 3 J/ 63,8 3,9 406,2 il ir

762 9 61.8 6.6 653.4 763 ir ~ 74.4 5.6 550.3 763 N02 0 74.4 5.6 550.3 * 764 + l 74.5 3.6 448.2 Y ## STR5 ## ./ "63.2 4.6 433.3 769 0 60.1 6.2 647.4 770T83.5 5.1 544.2 770 N02 0 83.5 5.1 544.2 tm <.Y" 68 , 1 4.1 432.3 771 T o 68.1 4.1 432.3 772 CH 3 J / 63.8 3.9 406.2 it ir

<Desc / Clms Page number 146>

773 0 41,1 5,8 620,4 774 r# 62,8 4,4 517,2 Nz 0 775 85,5 5,4 443,3 T bzz* 776 CH3 62,5 5,2 417,3 777 0 66,0 6,7 631,4 778 # 87,7 5,6 528,3 2 0

773 0 41.1 5.8 620.4 774 r # 62.8 4.4 517.2 NZ 0 775 85.5 5.4 443.3 T bzz * 776 CH3 62.5 5.2 417.3 777 0 66.0 6.7 631.4 778 # 87.7 5.6 528.3 2 0

<Desc / Clms Page number 147>

 Pharmacological Study The compounds of the present invention can and have been tested for their affinity for different somatostatin receptor subtypes according to the procedures described hereinafter.

Affinity study for human somatostatin receptor subtypes: The affinity of a compound of the invention for somatostatin 1-5 receptor subtypes (sst1, sst2, sst3, sst4 and sst5, respectively) is determined by measuring the inhibition of [125I-Tyr11] SRIF-14 binding to CHO-K1 transfected cells.

The human somatostatin sst1 receptor gene has been cloned as a genomic fragment. A 1.5 Kb PstI-XmnI segment containing 100 bp of the 5 'untranscribed region, 1.17 Kb of the entire coding region, and 230 bp of the untranscribed 3' region is modified by the addition of the linker. BglII. The resulting DNA fragment is subcloned into the BamHI site of a pCMV-81 to give the mammalian expression plasmid (provided by Dr. Graeme Bell, Univ.

Chicago). A cloned cell line stably expressing the ssti receptor is obtained by transfection into CHO-K1 (ATCC) cells by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as a selection marker. Cloned cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), cloned in a circle, and grown in culture.

The human somatostatin sst2 receptor gene, isolated as a 1.7 Kb BamHI-HindIII DNA genomic fragment and subcloned into a plasmid vector pGEM3Z (Promega), was provided by Dr. G. Bell. (University of Chicago).

The mammalian cell expression vector is constructed by inserting the 1.7 Kb BamH1-HindII fragment into compatible endonuclease restriction sites of plasmid pCMV5. A cloned cell line is obtained by transfection into CHO-K1 cells using the calcium phosphate co-precipitation method. The plasmid pRSV-neo is included as a selection marker.

The sst3 receptor is isolated as a genomic fragment, and the complete coding sequence is contained in a 2.4 Kb BamHI / HindIII fragment. The mammalian expression plasmid, pCMV-h3, is constructed by insertion of the 2.0 Kb NcoI-HindIII fragment into the EcoR1 site of the pCMV vector after modification of the termini and addition of EcoRI linkers. A cloned cell line expressing

<Desc / Clms Page number 148>

 stably the sst3 receptor is obtained by transfection into CHOK1 (ATCC) cells by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as a selection marker. Cloned cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), cloned in a circle, and grown in culture.

The human sst4 receptor expression plasmid, pCMV-HX, was provided by Dr. Graeme Bell (Chicago Univ.). This vector contains the genomic fragment coding for the 1.4 kb NheI-NheI human sst4 receptor, 456 bp of the 5 'untranscribed region, and 200 bp of the 3' untranscribed region, cloned into the XbaIlEcoRl sites of PCMV-1. HX. A cloned cell line stably expressing the sst4 receptor is obtained by transfection into CHO-K1 (ATCC) cells by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as a selection marker. Cloned cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), cloned in a circle, and grown in culture.

The gene corresponding to the human sst5 receptor, obtained by PCR using a genomic clone as a probe, was provided by Dr. Graeme Bell (Chicago Univ.). The resulting PCR fragment of 1.2 Kb contains 21 base pairs of the 5 'untranscribed region, the entire coding region, and 55 bp of the 3' untranscribed region. The clone is inserted into an EcoRI site of the plasmid pBSSK (+).

The insert is recovered as a 1.2 Kb HindIII-XbaI fragment for subcloning into a mammalian expression vector, pCVM5. A cloned cell line stably expressing the sst5 receptor is obtained by transfection into CHO-K1 (ATCC) cells by the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) is included as a selection marker. Cloned cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), cloned in a circle, and grown in culture.

The CHO-K1 cells stably expressing one of the human sst receptors are cultured in RPMI 1640 medium containing 10% fetal calf serum and 0.4 mg / ml geneticin. The cells are collected with 0.5 mM EDTA and centrifuged at 500 g for about 5 min at about 4 C. The centrifugate is resuspended in a 50 mM Tris buffer medium at pH 7.4 and centrifuged twice at 500 g. for about 5 min at about 4 C. The cells are lysed by sonication and centrifuged at 39000 g for about 10 min at 4 C. The centrifugate is re-suspended

<Desc / Clms Page number 149>

 in the same buffer medium and centrifuged at 50000 g for 10 min at about 4 C and the membranes in the centrifugate obtained are stored at -80 C.

Competitive binding inhibition assays with [125I-Tyr11] SRIF-14 are performed in duplicate using 96-well polypropylene plates. The cell membranes (10 g protein / well) are incubated with [125 I-Tyr II] SRIF-14 (0.05 nM) for about 60 min at about 37 ° C. in a 50 mM HEPES buffer medium (pH 7.4) comprising 0 , 2% BSA, 5 mM MgCl 2, 200 KIU / ml Trasylol, 0.02 mg / ml bacitracin and 0.02 mg / ml phenylmethylsulphonyl fluoride.

The bound [125I-Tyr11] SRIF-14 is separated from the free [125I-Tyr11] SRIF-14 by immediate filtration through GF / C fiberglass filter plates (Unifilter, Packard) pre-impregnated with 0.1% of polyethylenimine (PEL), using a Filtermate 196 (Packard). The filters are washed with 50 mM HEPES buffer at about 0-4 C for about 4 seconds and their radioactivity is determined using a counter (Packard Top Count).

Specific binding is obtained by subtracting the nonspecific binding (determined in the presence of 0.1 M SRIF-14) from the total binding. Linkage data are analyzed by computer-assisted non-linear regression analysis (MDL) and the values of the inhibition constants (Ki) values are determined.

The determination of the agonist or antagonist character of a compound of the present invention is carried out by means of the test described hereinafter.

Functional assay: Inhibition of intracellular cAMP production: CHO-K1 cells expressing human somatostatin receptor subtypes (SRIF-14) are cultured in 24-well plates in RPMI 1640 medium with 10% fetal calf serum and 0.4 mg / ml of geneticin. The environment is changed the day before the experiment.

The cells at the rate of 105 cells / well are washed twice with 0.5 ml of new RPMI medium comprising 0.2% BSA supplemented with 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX) and incubated for approximately 5 minutes. min at about 37 C.

. the production of cyclic AMP is stimulated by the addition of 1 mM forskolin (FSK) for 15-30 minutes at about 37 ° C.

<Desc / Clms Page number 150>

. the inhibitory effect of somatostatin of an agonist compound is measured by the simultaneous addition of FSK (1 M), SRIF-14 (10-12 M to 10-6 M) and the test compound (10 -10 M). at 10-5 M).

. the antagonistic effect of a compound is measured by the simultaneous addition of FSK (1 M), SRIF-14 (1 to 10 nM) and the test compound (10-10 M to 10-5 M).

The reaction medium is removed and 200 ml of 0.1 N HCl are added. The amount of cAMP is measured by radioimmunoassay (FlashPlate Kit SMP001A, New England Nuclear).

Results: The tests carried out according to the protocols described above made it possible to show that the products of general formula (I) defined in the present application have a good affinity for at least one of the somatostatin receptor subtypes, the inhibition constant Ki being less than the micromolar for some of the exemplified compounds.

Claims (14)

 R2 represents a radical of formula -C (Y) NHX, -C (O) X2 or SO2X3;

 or else R 1 represents a radical of formula

Z11 represents optionally substituted (C1-C6) alkyl or aryl, Z12 represents cyano, cyclohexenyl, bis-phenyl, (C3-C7) cycloalkyl, optionally substituted (C3-C7) heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, or Z12 represents a radical of formula  in racemic, enantiomeric form or any combination thereof, wherein: R represents a linear or branched (C1-C6) alkyl radical, alkenyl, alkynyl, - (CH2) mY-Z11 or - (CH2) n- Z12 in which

 1. Compounds of general formula <Desc / Clms Page number 152>

Z24 represents alkyl, cyclohexenyl, bis-phenyl, optionally substituted (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, cyano, amino, mono or di-alkylamino, or optionally substituted aryl or heteroaryl, or Z24 represents a radical of formula Z23 represents optionally substituted (C 1 -C 6) alkyl or aryl;  X2 represents a linear or branched (C1-C10) alkyl radical, alkenyl optionally substituted with a phenyl radical (the phenyl radical being itself optionally substituted), alkynyl, or a radical of formula - (CH2) mW- (CH2) q -Z23 or - (CH2) pU-Z24 in which

Z22 is cyclohexenyl, indanyl, bis-phenyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, mono- or di-alkylamino, -C (O) -O-alkyl, or optionally substituted aryl or heteroaryl, or Z22 represents a radical of formula Z21 represents a (C1-C6) alkyl  X 1 represents a linear or branched (C 1 -C 5) alkyl radical, alkenyl, alkynyl, - (CH 2) m -Y-Z 21 or - (CH 2) p Z 22 in which

 R3 represents the hydrogen atom, an optionally substituted alkyl radical, alkenyl, alkynyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, or a radical of formula -C (Y) -NHX ,, - (CH2) nC (O) X2; , S02X3 or <Desc / Clms Page number 153>  where the protecting group (GP) is H or tert-butyloxycarbonyl;

 or X 2 represents a radical represented below:

<Desc / Clms Page number 154>  / N "n, [O, S] optionally substituted by one or more identical or different halo radicals, Y represents an oxygen or sulfur atom, W represents an oxygen atom, sulfur atom or SO 2, U represents a covalent bond or the oxygen atom, n is an integer of 0 to 4, m is an integer of 1 to 6, p is an integer of 0 to 6, q is an integer of 0 to 2, or their salts addition with pharmaceutically acceptable mineral or organic acids.

Z25 represents optionally substituted aryl or heteroaryl, or X3 represents a radical of formula  X3 represents a linear or branched (C1-C10) alkyl radical, alkenyl optionally substituted by a phenyl radical (the phenyl radical being itself optionally substituted), CF3, or - (CH2) pZ25 in which 2. Compounds of general formula I as defined in claim 1, characterized in that i) the substituent (s) that can carry the aryl radicals that represent Z11 and Z12 and heteroaryl that represents Z12 are chosen independently from the radicals fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, -CF3, -OCF3, phenyl, phenoxy, aminosulfonyl; ii) the substituent (s) may carry the heterocycloalkyl radical represented by Z12 are independently selected from oxy and alkyl radicals; <Desc / Clms Page number 155>  iii) the substituent (s) may carry the aryl and heteroaryl radicals represented by Z22 are independently chosen from fluoro, chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido radicals; aminosulfonyl, piperidinosulfonyl, mono- or di-alkylamino, -C (O) -O-alkyl, -C (O) -alkyl, or phenyl, phenoxy, phenylthio, benzyloxy, the phenyl radical being substitutable; iv) the substituent (s) may carry the aryl radicals represented by Z 23 and Z 24, cycloalkyl and heteroaryl represented by Z 24 are independently chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF 3 and OCF 3 radicals, OCHF2, SCF3, nitro, cyano, azido, hydroxy, -C (O) O-alkyl, -OC (O) -alkyl, -NH-C (O) alkyl, alkylsulfonyl, mono- or di-alkylamino, amino, aminoalkyl pyrrolyl, pyrrolydinyl or the phenyl, phenoxy, phenylthio, benzyl or benzyloxy radicals, the aryl radical of which is optionally substituted with one or more alkyl, CF3 or halo radicals; v) the substituent (s) may carry the aryl and heteroaryl radicals represented by Z25 are independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, nitro, cyano, -NH-C radicals ( O) -alkyl, alkylsulfonyl, amino, mono- and di-alkylamino, phenyl, pyridino; vi) the substituent that can bear the alkyl radical that represents R3 is the cyano radical. vii) the substituent (s) may bear the aralkyl radical represented by R3 are independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, OCF3, OCHF2, SCF3, SCHF2, nitro, cyano, C (O) O-alkyl, alkylsulfonyl, thiadiazolyl, or the phenyl and phenoxy radicals, the phenyl radical of which is optionally substituted by one or more halo radicals. viii) the substituent (s) may bear the heteroarylalkyl radical represented by R3 are independently selected from fluoro, chloro, bromo or nitro radicals. 3. Compounds of general formula I as defined in one of claims 1 to 2, characterized in that <Desc / Clms Page number 156>

Z12 represents bis-phenyl, (C3-C7) cycloalkyl, (C3-C7) optionally substituted heterocycloalkyl, or aryl or heteroaryl optionally substituted with one or more substituents chosen independently from fluoro, chloro, bromo, iodo, alkyl or alkoxy radicals, or else Z12 represents Z11 represents a (C1-C6) alkyl,  R1 represents a linear or branched (C1-C6) alkyl radical, the radical - (CH2) m -Y-Z11 or - (CH2) m -Z12 in which W represents SO2,  X2 represents a linear or branched (C1-C10) alkyl radical, alkynyl, - (CH2) m -W- (CH2) q-Z23 or - (CH2) p-U-Z24 in which

Z22 is cyclohexenyl, bis-phenyl, (C3-C7) cycloalkyl, (C3-C7) heterocycloalkyl, mono- or di-alkylamino, -C (O) -O-alkyl, or aryl or heteroaryl optionally substituted with one or more radicals. independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulfonyl, -C (O) -O-alkyl, -C (O) -alkyl, or phenyl, or Z22 represents a radical of formula X represents a linear or branched (C1-C15) alkyl radical, or- (CH2) pZ22 in which  R2 represents a radical of formula -C (Y) NHX ,, -C (O) X2 or SO2X3 in which

Y represents the oxygen atom, or R represents a radical of formula <Desc / Clms Page number 157>

 or else X2 represents

 U represents a covalent bond, Z23 represents an aryl radical; Z24 represents cyclohexenyl, bis-phenyl, (C3-C7) cycloalkyl optionally substituted by an aminoalkyl radical, or aryl or heteroaryl optionally substituted by one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, -CF3, - OCF3, SCF3, hydroxy, -OC (O) -alkyl, mono- or di-alkylamino, amino or Z24 represents a radical of formula Z22 represents an aryl radical optionally substituted by one or more radicals chosen independently from fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals; X1 represents a radical - (CH2) pZ22 in which X3 represents a - (CH2) pZ25 radical in which Z25 represents an aryl radical optionally substituted with one or more identical or different radicals chosen from alkoxy and CF3, R3 represents the hydrogen atom, an optionally substituted alkyl, alkenyl or heteroarylalkyl radical; or a radical of formula -C (Y) -NHX1, -C (O) X2 or SO2X3 in which <Desc / Clms Page number 158>

 X 2 represents the vinyl radical substituted by a phenyl, the phenyl radical being itself optionally substituted with one or more halo radicals, or - (CH 2) pU-Z 24 in which Z 24 represents alkyl, (C 3 -C 7) cycloalkyl, (C 3 C7) heterocycloalkyl, bisphenyl, amino, mono or di-alkylamino, or aryl or heteroaryl optionally substituted by one or more radicals selected from alkoxy, bromo, chloro, fluoro, hydroxy, CF3, nitro, amino, mono- and di- alkylamino, pyrrolyl, or X2 represents a radical of formula Z25 represents aryl or heteroaryl optionally substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, -NH-C (O) -alkyl, mono- and di-alkylamino radicals. X3 represents a linear or branched (C1-C10) alkyl radical, the vinyl radical substituted by a radical (the phenyl radical being itself optionally substituted), CF3, or - (CH2) pZ25 in which 4. Compounds of formula I as defined in one of claims 1 to 3, characterized in that R1 represents a linear or branched (C1-C6) alkyl radical, the radical - (CH2) mY-Z11 or - (CH2 ) m-Z12 in which Z11 represents a (C, -C6) alkyl, <Desc / Clms Page number 159>

 Z12 represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl substituted by the oxy radical, or the phenyl, piperazinyl, pyridinyl and indolyl radicals which are optionally substituted with one or more substituents chosen independently from the bromo, fluoro, chloro, alkyl radicals, alkoxy, -CF3, -OCF3; or else Z12 represents Z23 represents the phenyl radical; W represents SO2;  X2 represents an alkyl radical, alkynyl, - (CH2) m -W- (CH2) q-Z23 or - (CH2) pZ24 in which

Z22 represents cyclohexyl, cyclohexenyl, bis-phenyl, morpholino, piperidino, mono- or di-alkylamino, -C (O) -O-alkyl, or phenyl, naphthyl or furyl optionally substituted with one or more radicals chosen independently from the fluoro radicals; , chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF3, OCF3, nitro, cyano, azido, piperidinosulfonyl, -C (O) -O-alkyl, -C (O) -alkyl or phenyl, or Z22 represents a radical of formula X1 represents a linear or branched (C1-C10) alkyl radical, or- (CH2) pZ22 in which  R2 represents a radical of formula -C (Y) NHX1, -C (O) X2 or SO2X3 in which

Y represents the oxygen atom, or R1 represents a radical of formula: <Desc / Clms Page number 160>

 or else X2 represents

 Z 24 represents cyclohexenyl, bis-phenyl, cyclohexyl optionally substituted by an aminoalkyl radical, or phenyl, naphthyl, benzothienyl, thienyl or indolyl optionally substituted with one or more radicals chosen from fluoro, chloro, bromo, iodo, alkyl, alkoxy, -CF3, OCF 3, SCF 3, hydroxy, -OC (O) -alkyl, -NH-C (O) -alkyl, mono- or di-alkylamino, amino, or Z 24 represents a radical of formula Z22 represents the phenyl or naphthyl radical optionally substituted with one or more radicals chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, phenoxy radicals, X represents a radical - (CH2) pZ22 in which X3 represents a - (CH2) pZ25 radical in which Z25 represents the phenyl radical optionally substituted with one or more identical or different radicals chosen from alkoxy and CF3, R3 represents the hydrogen atom, an alkyl, alkenyl or furyl-methyl radical; substituted by one or more nitro radicals, or a radical of formula -C (Y) -NHX1, C (O) X2 or SO2X3 in which <Desc / Clms Page number 161>

 X 2 represents the vinyl radical substituted by a phenyl radical, itself optionally substituted with one or more halo radicals, or - (CH 2) pU-Z 24 in which Z 24 represents alkyl, cyclohexyl, tetrahydrofuryl, bis-phenyl, amino, mono or di- alkylamino, or phenyl, indolyl, thienyl, pyridinyl, benzothienyl and furyl optionally substituted by one or more radicals selected from alkoxy, bromo, chloro, fluoro, amino, mono- and di-alkylamino, nitro, hydroxy, pyrrolyl or X2 represents a radical of formula Z25 represents a phenyl, naphthyl, thienyl, pyrazolyl or thiazolyl radical optionally substituted by one or more substituents chosen independently from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF3, nitro, -NH-C (O) -alkyl radicals; mono- and di-alkylamino; 5. Compounds of formula 1 as defined in one of claims 1 to 4, characterized in that R, represents the radical - (CH2) mZ12 in which m = 2 and Z12 represents bis-phenyl or the substituted indolyl radical by one or more substituents independently selected from alkyl and alkoxy radicals. X3 represents a linear or branched (C1-C10) alkyl radical, the vinyl radical substituted by a phenyl radical, CF3, or - (CH2) pZ25 in which 6. Compounds of formula I as defined in one of claims 1 to 5, characterized in that R2 represents the radicals of formula -C (Y) NHX, and -C (O) X2 in which Y is S; <Desc / Clms Page number 162> Z24 represents cyclohexyl, or phenyl or benzothienyl optionally substituted with one or more radicals selected from fluoro, chloro, bromo, iodo or -CF3. X2 is - (CH2) pZ24 wherein p is 1, 2 or 3, X 1 represents a phenyl radical optionally substituted with one or more azido radicals, 7. Compounds of formula I as defined in one of claims 1 to 6, characterized in that R3 represents the hydrogen atom or the methyl radical. 8. Process for the preparation, in the liquid phase, of compounds of formula I as defined in claim 1, characterized in that it comprises the reductive amination of the following N-substituted piperidone

 in which R represents the methyl radical or Boc, in the presence of an amine of formula R1NH2 in which R1 has the meaning indicated in claim 1, to obtain the compound of formula 1

 compound of formula (1) which is reacted with A) is a compound of formula X1NC (Y) wherein X, and Y have the meaning indicated in claim 1, to obtain a compound of formula (2) <Desc / Clms Page number 163>  compound of formula (3) which represents the corresponding compound of formula (I) wherein R3 is Me or Boc and which, when R3 is Boc, may be acid treated to obtain the corresponding compound of formula (I) wherein R3 represents the hydrogen atom, compound of formula (I) thus obtained which can be reacted with a compound of formula X, NC (Y), X2CO2H or X3SO2Cl wherein X ,, Y, X2 and X3 have the meaning indicated in claim 1, to obtain the corresponding compound of formula I wherein R2 represents a radical of formula -C (O) X2 and R3 the radical-C (Y) -NHX1, -C (O) X2 or S02X3 respectively.

 compound of formula (2) which represents the corresponding compound of formula (I) wherein R3 is Me or Boc and which, when R3 is Boc, may be subjected to acid treatment to obtain the corresponding compound of formula (I) in which R3 represents the hydrogen atom, compound of formula (I) thus obtained which can be reacted with a compound of formula X1NC (Y), X2CO2H or X3SO2Cl wherein X1, Y, X2 and X3 have the meaning as claimed in claim 1, to give the corresponding compound of formula I wherein R2 represents a radical of formula -C (Y) NHX, and R3 the radical-C (Y) -NHX1, -C (O) X2 or SOZX3 respectively ; B) a compound of formula X2CO2H wherein X2 has the meaning indicated in claim 1, to obtain a compound of formula (3)

<Desc / Clms Page number 164> 9. Process for the preparation, in solid phase, of compounds of formula I as defined in claim 1, characterized in that it comprises the reductive amination of the ketonic resin.

 in the presence of an amine of formula R 1 NH 2 in which R 1 has the meaning indicated in claim 1, to obtain the compound of formula (4)

 compound of formula (4) which is reacted with A) is a compound of formula X, NC (Y) wherein X1 and Y have the meaning indicated in claim 1, to obtain a compound of formula (5)

 followed by cleavage of the resin to obtain the compound of formula (I) in which R3 represents hydrogen, B) is a compound of formula X3SO2Cl wherein X3 has the meaning indicated in claim 1, to obtain a compound of formula (6) <Desc / Clms Page number 165>  followed by cleavage of the resin to obtain the corresponding compound of formula (I) wherein R3 represents hydrogen; D) a compound of formula X2CO2H wherein X2 has the meaning indicated in claim 1, to obtain a compound of formula (7) as defined above, followed by cleavage of the resin to obtain the compound of formula (I ) in which R3 represents the hydrogen atom.

 followed by cleavage of the resin to obtain the corresponding compound of formula (I) wherein R3 represents hydrogen, C) is a compound of formula X2CO2Cl wherein X2 has the meaning indicated in claim 1, to obtain a compound of formula (7)

10. Process for the preparation, in the solid phase, of compounds of formula I as defined in claim 1, characterized in that it comprises the reductive amination of the ketonic resin.

<Desc / Clms Page number 166>  compound (10) thus formed which is reacted with a compound of formula R3X wherein R3 is as defined in claim 1 and X is Br or I followed by cleavage of the resin to obtain the compound of formula (I ) corresponding;

 compound (9) thus formed which is reacted with a compound of formula R3X wherein R3 is as defined in claim 1 and X is Br or I, followed by cleavage of the resin to obtain the compound of formula (I ) corresponding; B) a compound of formula X3SO2Cl wherein X3 has the meaning indicated in claim 1, to obtain a compound of formula (10)

 compound of formula (8) which is reacted with A) is a compound of formula X1NC (O) wherein X1 has the meaning indicated in claim 1, to obtain a compound of formula (9)

 in the presence of an amine of formula R1NH2 wherein R, has the meaning indicated in claim 1, to obtain the compound of formula (8) <Desc / Clms Page number 167>  compound (11) thus formed which is reacted with a compound of formula R3X wherein R3 is as defined in claim 1 and X is Br or I, followed by cleavage of the resin to obtain the compound of formula (I ) corresponding; D) a compound of formula X2CO2H wherein X2 has the meaning indicated in claim 1, to obtain a compound of formula (11) as defined above, compound (11) thus formed which is reacted with a compound of formula R3X wherein R3 is as defined in claim 1 and X is Br or I, followed by cleavage of the resin to obtain the corresponding compound of formula (I).

 C) a compound of formula X2CO2Cl wherein X2 has the meaning indicated in claim 1, to obtain a compound of formula (11) 11. As medicaments, the products of formula I as in one of claims 1 to 7, as well as addition salts with pharmaceutically acceptable inorganic or organic acids of said products of formula I. 12. Pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined in claim 11, in combination with a pharmaceutically acceptable carrier. 13. Use of a compound of formula 1 as defined in one of claims 1 to 7 for the preparation of a medicament for treating disease states or diseases in which one (or more) of the somatostatin receptors is (are) involved. 14. Use according to claim 13 for the preparation of a medicament for treating acromegaly, pituitary adenomas or endocrine gastroenteropancreatic tumors including carcinoid syndrome. <Desc / Clms Page number 168>  wherein R 1, R 2 and R 3 represent various variable groups, their methods of preparation by liquid and solid phase parallel synthesis methods. Since these products have a good affinity with certain somatostatin receptor subtypes, they are particularly useful for treating pathological conditions or diseases in which one or more somatostatin receptors are (are) involved.

 The present application relates to novel derivatives of 4-aminopiperidines of the formula